Physiology Exam I

Rebecca, practice slides 31 to 36 of membrane potential lecture

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How does the shape of action potentials differ between cardiac cells and neurons/skeletal muscle cells? What does this imply overall?

-cardiac cells have a much wider action potential with a plateau due to the involvement of Ca2+. Neurons and skeletal muscle cells don't have this plateau phase. -different action potential waveforms indicate different ionic mechanisms

What are the two main ways the alpha-1 receptor can be exploited therapeutically?

-cases of hypotension - treated using alpha-1 receptor activation -cases of hypertension - treated using antagonists/blockers of alpha-1 receptor

How do excitatory hormones/neurotransmitters work on smooth muscle? List the smooth muscle excitatory chemicals.

-cause smooth muscle to contract by increasing the amount of calcium or affect myosin phosphorylation. -angiotensin II -endothelin -vasopressin -norepinephrine -thromboxane

How do inhibitory hormones/neurotransmitters work on smooth muscle? List the smooth muscle inhibitory chemicals.

-cause smooth muscle to relax by decreasing the amount of calcium or affect myosin phosphorylation. -adenosine -epinephrine -hydrogen sulfide -hypoxia -nitric oxide

Nephrogenic diabetes insipidus

-caused by mutations in aquaporin-2 gene, which prevents insertion of aquaporin channels -Patients have low/no density of aquaporins -Normally, ADH binds to its receptor, adenylate cyclase is activated, and aquaporins are inserted. This is affected in this disease. -affected patients produce a large amount of dilute urine (aquaporins are non-functional. You need aquaporins in collecting ducts for re-absorption/producing concentrated urine) -extreme thirst

What is characteristic of single unit smooth muscle?

-cells contract in unison -often found in GI tract or urogenital tract -signal from diffuse junction is communicated to adjacent cells. -Gap junctions facilitate this cell-to-cell communication in single-unit smooth muscle. -Gap junctions can pass ions (e.g. Ca2+) or can pass depolarization of cell membrane.

Passive transport

-do not require energy -simple diffusion through lipid bilayer -diffusion through channels -facilitated diffusion (needs uniporter)

What is an important characteristic of the autonomic nervous system?

-dual innervation -visceral organs (eye, heart, etc) receive dual innervation (meaning fibers from the sympathetic and parasympathetic divisions) -This is not redundant - the two divisions produce opposing physiological outcomes and act through different receptors/mechanisms.

What are some cholinesterase (i.e. acetylcholinesterase) inhibitors that can be used on the NMJ? Which ones are irreversible?

-edrophonium = a short acting inhibitor for use in diagnosing myasthenia gravis -neostigmine = longer acting, used for treatment of myasthenia gravis -organophosphorus (pesticide) compounds and nerve gases = irreversible

Define ergotrophic and trophotropic. What systems do they activate? Where do we typically function?

-ergotropic = fight or flight response. Leads to activation of sympathetic system. -trophotropic = rest and digest response. Leads to activation of parasympathetic system -Ergotropic and trophotropic are two extremes. We want something in between most of the time.

Uniporter - definition, characteristics, and example

-facilitated (passive) diffusion - protein carrier transports only one substance *down its concentration gradient* -faster than simple diffusion -there is a Vmax - achieved when the concentration gradient across membrane is very large and each uniporter is working at maximum rate. Depends on number of uniporters in membrane. -speed of diffusion depends on concentration gradient -transport direction is reversible (depends on which way the concentration gradient is) -each uniporter type is specific to a single type of molecule or group of closely related molecules -Km - affinity of a transporter for its substrate. Recall Km = concentration at 1/2*Vmax. -can't go against concentration/elecrochemical gradient -*example* = GLUT1 transporter

What are the levels of connective tissue that help to organize/anchor the contractile proteins that allow you to produce force with muscle?

-first layer = epimysium - beneath/distinct from a sheath of fascia; outermost layer that can attach directly to bone or indirectly to bone via tendon/aponeurosis; goes all the way around muscle belly. -second layer = perimysium - surrounds individual fascicles; helps to stabilize them and vascular network; has venules, arterioles, and nerves running through it. -third layer = endomysium - surrounds muscle fibers; innermost layer; stabilizes capillary network and nerves innervating muscle cells.

Describe tonically active smooth muscle and give an example. Describe how membrane potential changes.

-found in blood vessels - always contracted to some degree. -Modulate level of contraction up or down depending on needs -e.g. increasing or decreasing blood pressure, or increasing or decreasing caliber of airways -In these cases, you don't necessarily have action potentials fired. The amount of force generated by that smooth muscle is going to be solely affected by oscillations in membrane potential that have nothing to do with actual generation of action potentials. Oscillations in membrane potential are mirrored by oscillations in amount of force produced by that smooth muscle.

What is the function of electrical synapses?

-found in most types of tissues (nervous system, myocardial cells, intestinal smooth muscle, cochlea) -mediate chemical coupling in a network -synchronize electric activity among populations of neurons

What are the two strategies fro producing graded muscle contraction?

-frequency summation -motor unit recruitment

What are the amino acid neurotransmitters and their receptors? What does each one do?

-glutamate = primary excitatory neurotransmitter of this group. Receptors called mGluRs (include AMPA, kainate, and NMDA classes). -GABA = the major inhibitory transmitter in the CNS. Receptors are the GABA-A receptor (Cl- channel) and GABA-B receptor (K+ or Ca2+ channels). -glycine - glycine receptor is a Cl- channel. An inhibitory neurotransmitter. -serine -aspartate - excitatory

What are the specialized ganglia? What would happen if you surgically removed one of these ganglia?

-superior cervical -celiac -superior mesenteric -inferior mesenteric -If you surgically remove a specialized ganglion, you have the potential to affect a lot of downstream organs.

What is the weird exception to sympathetic division neurotransmitters?

-sympathetic sweat glands -post-ganglionic fiber is a sympathetic fiber. -BUT on the surface of the organ, there's release of acetylcholine and muscarinic receptors.

Primary active transport - sodium/potassium pump

-takes 3 sodium out, brings 2 potassium in -direct use of ATP -goes against ion gradient. However, it also maintains the membrane gradient at the same time. Na+ and K+ constantly leak down their concentration gradients and this pump counter-acts that so that the gradient doesn't collapse. -needed to maintain membrane potential and prevent cell swelling -important to brain functioning (running this pump accounts for a large portion of brain's energy consumption) -can be blocked by ouabain and digoxin. Note that ouabain does not take immediate effect because it takes a while for the gradient to collapse (meaning it takes a while for sodium and potassium levels to balance out). -NOT part of ABC superfamily

How does conduction velocity relate to the length constant and the time constant?

-the conduction velocity of action potentials is directly proportional to the length constant (lambda. The bigger the length constant, the better because this means it takes longer for the stimulus to decay). -the conduction velocity of action potentials is inversely proportional to the time constant (tau = resistance*capacitance, don't need to know equation. Remember tau is the time it takes to charge a capacitor. It makes sense that it takes less time to charge if velocity is higher). -To reiterate, conduction velocity is proportional to the square root of axon radius (e.g. radius of 4 has speed of 2. To double the speed, you'll have to quadruple the radius).

What are the contractile elements of a muscle cell?

-thin filaments (actin) -thick filaments (myosin) -titin - a large molecular protein

Where are post-synaptic sites located? Where AREN'T they found?

-throughout soma and dendrite -NOT ON AXON

What effect would overstimulation of M3 receptors on glands have?

-too much M3 secretion paints a wet picture - too much lacrimation, salivation, GI secretion, urination, etc.

What are some nicotinic (acetylcholine) receptor blockers in the NMJ? Which one is irreversible?

-tubocurarine -curare -alpha-bungarotoxin - irreversibly blocks Ach receptors

Explain the accessory pathway of catecholamine synthesis.

-tyramine converted to octopamine and then made into norepinephrine (and eventually epinephrine)

What is the rate limiting enzyme of catecholamine synthesis? What is the key neurotransmitter secreted from the adrenergic nerve terminal? What is the exception to this?

-tyrosine hydroxylase = rate-limiting enzyme -norepinephrine is the key neurotransmitter secreted from the nerve terminal -BUT in the adrenal medulla, norepinephrine can be converted to epinephrine too.

What are nodes of Ranvier? What is found there?

-unmyelinated areas between myelin sheath chunks -Na+ channels aggregate in nodes of Ranvier (not an even distribution of channels, unlike unmyelinated axons)

Na+/H+ exchanger

1:1 exchange of Na+ and H+. Na+ moves in cell and H+ goes out.

What is serotonin's receptor?

5-HT receptors (note that serotonin is a biogenic amine, but is not a catecholamine)

Describe normally contracted smooth muscle and give an example.

= sphincter muscles - contracted all the time and only periodically releases -e.g. stomach - you want to keep things inside the stomach while stuff is being mixed there and let it leave when it's appropriate.

Interpretation of Nernst potential

*The value of a (hypothetical) membrane potential, which would prevent any net diffusion of the ion. So, it is a hypothetical electrical force equal and opposite to the chemical driving force due to the chemical gradient. This is why Ek represents the strength of the chemical force on the ion.*

What is type I muscle fiber?

-"slow twitch oxidative muscle" -highly oxidative fiber types -depend primarily on *aerobic* oxidation for ATP production -not particularly rapid to generate force, but can generate force for a long period of time without fatiguing (stays relatively constant)

What is the #1 treatment choice in asthma and COPD? Why?

-*activating beta-2 receptors is the #1 treatment of choice in asthma and COPD* -Beta-2 adrenergic receptors are very abundant on the bronchiolar smooth muscle. If you activate these receptors, you will have increased cAMP in the bronchiolar smooth muscle and (through a host of different mechanisms) you will cause relaxation of the bronchiolar smooth muscle. -So, increases in cAMP in the vascular/bronchiolar smooth muscle act in a different way than increases in cAMP in the cardiac muscle.

Factors affecting rate of simple diffusion (What's the major driving force?)

-*major driving force* = concentration gradient (greater the difference, faster the diffusion) -lipid solubility (increased solubility = increased permeability) -molecular size (bigger doesn't diffuse well) -cell membrane thickness (as membrane thickness increases, diffusion decreases) -membrane surface area (larger the surface area, the larger the rate of net diffusion) -composition of lipid bilayer

Where are all the nicotinic receptors located? What happens if you activate nicotinic receptors strongly?

-All of the nicotinic receptors are *on the ganglia* -If you activate nicotinic receptors very potently, everything will be stimulated downstream. You'll activate all the post-ganglionic fibers. The end result depends on what receptor is on what organ (and the abundance of those receptors).

What causes asthma and how can you treat it?

-An allergen causes an immune response and reflex activation of airway smooth muscle -Treatment of asthma can be done by stimulation of beta-2 adrenergic receptors in bronchial smooth muscles. This causes that smooth muscle to relax and bronchodilation. -You can also use anticholinergic agents, which attenuate acetylcholine-mediated reflex excitation and allow bronchodilation.

What causes reflex bradycardia and reflex tachycardia?

-An increase in total peripheral resistance (alpha-1 activation) causes reflex bradycardia -A decrease in total peripheral resistance (alpha-1 inhibition) causes reflex tachycardia

What happens in hypocalcemia?

-As [Ca2+] outside the cell decreases, the amount of depolarization (i.e. threshold) required to generate an action potential is decreased. -Threshold for action potential is decreased in a hypocalcemic state, making it easier to generate an action potential -Sometimes the threshold is decreased so much that simply the resting membrane potential alone can generate action potentials

How does membrane permeability change during an action potential?

-At resting state, membrane permeability to K+ ions is higher than Na+. -At action potential, it shifts to permeability to Na+ -During the re-polarization phase, permeability changes back to favor K+

Describe the generation of autonomic impulses

-Autonomic impulses are initiated in the brainstem and then travel via the intermediolateral column of the spinal cord, where they will synapse in a variety of different ganglia.

What systems does the ANS belong to? What are its divisions?

-Autonomic nervous system belongs to the central and peripheral nervous systems -Autonomic nervous system is divided further into 3 branches: -sympathetic division -parasympathetic division -enteric division - has inputs from both the sympathetic and parasympathetic divisions. But it can function without those inputs too.

What area of the neuron has the highest density of voltage-gated Na+ channels with the lowest threshold for generating action potentials? Why is this important for action potential generation?

-Axon hillock/initial segment (this is the initial part of the axon/most proximal) -Ensures the action potential will always begin in the hillock/initial segment and then propagate to the axon terminal

What G protein are beta-1 and beta-2 receptors coupled with? What happens when you activate these receptors?

-Beta-1 and beta-2 receptors are coupled with a Gs (stimulatory) protein. -Activation of beta-1 and beta-2 receptors by binding of norepinephrine or epinephrine then activates Gs. -Gs's alpha subunit will then activate adenylyl cyclase, which causes an increase in cAMP. -cAMP has different effects depending on the organ where it is at. High cAMP leads to increased PKA activity downstream

Explain how using an inhaler with a beta-2 agonist can treat asthma.

-Beta-2 agonist binds to its receptor and activates adenylate cyclase on membrane. -This is coupled with a G protein coupled receptor. We then have increased cAMP levels and increased protein kinase A activity. -Protein kinase A then goes on to phosphorylate targets that are important to excitation of the cell. -Protein kinase A causes phosphorylation of calcium activated K+ channels, which affects membrane potential. -Protein kinase A downregulates IP3 second messenger pathway (and therefore decreases release of Ca2+ from sarcoplasmic reticulum) -Protein kinase A activates membrane bound pumps that get Ca2+ out of the cytoplasm -Protein kinase A can directly modulate (inhibiting) the activity of myosin light chain kinase -Net effect = smooth muscle relaxation/bronchodilation.

Differences between action potential and EPSP.

-Biggest difference between EPSP and action potential - EPSP is a local potential and its propagation is decremental (voltage response decreases with distance). An action potential, by contrast, can do active conduction. -This is because we have different key players. Action potential = voltage gated Na+ channels. EPSP = ligand gated ion channel.

How does botulinum toxin target NMJ SNARE proteins?

-Botulinum toxin can cleave SNARE proteins. -Cleavage compromises the process of bringing the vesicle close to the plasma membrane and subsequent vesicle fusion with the membrane. -Functionally, without presynaptic neurotransmitter release, you will not be able to activate the post-synaptic receptor. If this is at the NMJ, you won't be able to move your muscles and you'll be weak.

How does vesicle endocytosis (vesicle recycling) work in the recovery phase? Does the vesicle content (neurotransmitter) get endocytosed?

-Clathrin mediated process - adaptor proteins connect clathrin to vesicular membrane. A clathrin coat/pit forms. Dynamin pinches off the clathrin coated vesicle. Clathrin is then removed from vesicle. -NO, the vesicle content does NOT get endocytosed. This kind of endocytosis is not effective at getting the neurotransmitter in. This is because once the neurotransmitter enters the cleft, it diffuses away and its concentration by the pre-synaptic terminal will be minimal. Also, this is not a receptor-mediated endocytosis so neurotransmitter won't be binding to the membrane that will be endocytosed.

Explain gap junction structure. What can go wrong with this?

-Connexins = building blocks -6 connexins make 1 connexon -A connexon is a semi-channel that doesn't function unless it is lined up with another semi-channel. This makes a gap junction. -Each side of the membrane contributes one semi-channel to form a functional gap junction. -A variety of genetic diseases are linked to mutations of one of the 20+ connexin genes.

What is cotransmission? What do small granular vesicles contain and what is their function? What do large granular vesicles contain and what is their function? Define neuromodulator. What happens if you take away a neuromodulator?

-Cotransmission - there is more than one neurotransmitter secreted from a given nerve (there are many) -Figure shows sympathetic nerve varicosity and vascular smooth muscle. -Small granular vesicles contain ATP or norepinephrine. When secreted, they work to activate their own receptors to cause an increase in calcium and smooth muscle contraction -At the same time, this same nerve contains large granular vesicles, which contain a lot of neuropeptide- Y. Neuropeptide-Y, in addition to being a neurotransmitter, also works as a neuromodulator. -Neuromodulators come back and inhibit the secretion of norepinephrine and ATP from the small granular vesicles. -If you take away neuropeptide-Y, you could have increased secretion of ATP and norepinephrine. So blood pressure might increase as a result.

Compare and contrast the cross bridge cycle in smooth muscle and skeletal muscle.

-Cross bridge cycle is basically the same in smooth muscle as in skeletal muscle -Need ATP to come in, hydrolyze ATP, and cock back myosin head -The one thing that's different in cross bridge cycle of smooth muscle = in order for the myosin head and actin to interact, myosin light chain in hinge must be phosphorylated. -The rest of the cycle is the same.

What is the enteric nervous system? What can input into this system? What are its two plexuses?

-Enteric nervous system - a system of ganglia sandwiched between layers of the gut. In between the layers - a system of many different nerves with different functions. -Receives input from the sympathetic and parasympathetic divisions of the ANS. Can also function normally without this input. -Two plexuses = -myenteric/Auerbach's plexus is sandwiched between the longitudinal muscle of the external muscular layer and the deeper circular muscle. Controls motility of the gut. (Myenteric, motility) -submucosal/Meissner's plexus is located between the circular muscularis mucosae. Submucosal plexus controls ion and fluid transport. Activity of the submucosal plexus controls the secretion of glands.

How does Ca2+ sensitivity influence action potential threshold?

-Extracellular Ca2+ (NOT Ca2+ channels) influences action potential threshold by changing Na+ channel open probability. -Under normal conditions, as membrane voltage depolarizes, the open probability of Na+ increases. -If you have hypocalcemia, the curve shifts left. Note how at -30 mV, nearly 100% of channels are open. -If you have hypercalcemia, the curve shifts right. Note how at -30 mV, only about 5% of channels are open.

What does the sacral outflow innervate? What happens if you have damage to the sacral outflow?

-Fibers control bladder, descending large intestine, rectum, and genitalia -Trauma affecting S3-S4 could affect the bladder, intestines, rectum, and genitalia (disorders with sexual activity, e.g.)

Compare and contrast axons, neurotransmitters, and control of the somatic nervous system vs the autonomic nervous system in the PNS.

-For the somatic nervous system - you have the nerve body in the CNS and going to the effector organ via one big long axon. Neurotransmitter secreted = acetylcholine. You can control this system by telling your muscle what to do. -For the autonomic nervous system - you have something in between the CNS and the effector organ (AKA 2 axons and a ganglion). Neurotransmitters vary and there is no conscious control.

How does treating a patient's hypertension with adrenergic receptor agonists act as an example of denervation supersensitivity/withdrawal rebound hyperactivity/disuse hyperactivity?

-If a patient is on beta blockers, but wants to change to another class of drugs, you have to be careful. -Changing to another class of drugs can cause withdrawal rebound hyperactivity (rebound HTN) due to an increase in adrenergic receptors while using the drug. -A better way to change drug = taper the beta blockers down to avoid rebound HTN. KNOW THIS.

What happens to blood pressure, heart rate, cardiac output, contraction of skeletal muscle, and blood sugar when you activate sympathetics? Why?

-If you activate sympathetics, you increase blood pressure (through beta-1 and alpha-1), heart rate, cardiac output, contraction of skeletal muscle, blood sugar -you do this to prepare your body for a fight or flight response

Why do patients with myocardial ischemia benefit from beta-blockers?

-If you block beta-1 - heart rate will go down, contractility will go down, and there will be less oxygen consumption (heart needs less blood supply) -Ischemic tissue doesn't want to use a lot of oxygen so this is beneficial

What would happen if you overactivate the submucosal plexus of the enteric nervous system?

-If you over-activate this system, you can get abdominal cramping and more secretions. This causes "a wet picture" (increased secretion, which may then be followed by diarrhea)

How can you use withdrawal rebound hyperactivity as a way to test autonomic functions?

-If you see excessive response to low-dose stimulators, there might be some autonomic disorder that should be looked into.

Why can beta blockers be used to treat arrhythmias?

-If you stimulate Purkinje tissues strong enough, you can get an abnormal impulse. If that is propagated, you can get arrhythmia. -Beta-blockers can treat arrhythmia because you suppress the automaticity of the abnormal Purkinje fibers.

What complaints may a male patient have who is on an alpha-1 receptor blocker to treat hypertension?

-If you use alpha-1 receptor blocker to treat hypertension, your patient may have ejaculatory difficulty because alpha-1 stimulates ejaculation by the vas deferens.

Say you give an alpha-1 adrenergic receptor antagonist to a patient that is coming in for an acute increase in their chronic hypertension. They have a past history of myocardial ischemia from high blood pressure. Why might the patient experience chest pain when you give them an alpha-1 inhibitor?

-If you use an alpha-1 adrenergic receptor antagonist to decrease blood pressure fast, you will see heart rate increase (reflex tachycardia). -As a result, the oxygen demand of the heart increases. The patient may develop chest pain.

What would you expect to see happen to TPR, blood pressure, and heart rate if you gave the patient an alpha-1 adrenergic receptor agonist? What would happen if you inhibited alpha-1?

-If you were to give a patient an alpha-1 adrenergic receptor agonist, you would see increased TPR and thus increased blood pressure. Blood pressure will go up right away. To compensate, the body will drop heart rate. -If you drop blood pressure by inhibiting alpha-1 adrenergic receptor, you would see reflex tachycardia

What might prevent you from seeing reflex tachycardia when blood pressure drops (as a result of inhibiting alpha-1 receptors)?

-If your patient has been using a beta adrenergic receptor blocker, you may not see reflex tachycardia because part of the pathway has been blocked. -In other words, the beta adrenergic receptors must be intact for reflex mechanisms to work.

What are caveolae in smooth muscle? What are they analogous to in skeletal muscle?

-Invaginations of cell membrane in smooth muscle are called caveolae. Caveolae are just pits (unlike in skeletal muscle where these invaginations dive deep into the cell via T tubules). -Caveolae increase surface area and are lined with receptors for neurotransmitters and hormones - This is an important part of cell signaling in smooth muscles.

What is the function of invaginations in the sarcolemma? What are they also called?

-Invaginations of the cell membrane are periodically present throughout the cell membrane (AKA the sarcolemma). These invaginations penetrate into the muscle cells and form tubes called transverse tubules (T-tubules, extensions of plasma membrane). -Important for transmission of neural impulses (i.e. T tubules help transmit depolarizations into myofibrils of cell)

What is a fascicle?

A bundle of muscle fibers

In vitro experiment - 10 mM KCl in chamber 1 and 1 mM KCl in chamber 2. Membrane between chambers is only permeable to K+. What happens?

-K+ flux is driven in one direction by chemical gradient across membrane (from chamber 1 to 2). -K+ flux results in a charge difference and thus a voltage across the membrane. This creates an electrical driving force. -K+ flux is driven in the opposite direction by this membrane voltage (i.e. electrical driving force is pushing from chamber 2 to 1) -electrochemical equilibrium (Ek) is achieved at the voltage where the electrical and chemical fluxes balance. -In other words, K+ diffuses out of chamber 1 until the chemical driving force (due to concentration gradient) is opposed by sufficient electrical driving force (due to membrane potential) to prevent any more net diffusion.

What are ionotropic receptors? How do they work?

-Ligand gated ion channels on post-synaptic membrane. Ligand is a neurotransmitter from the synaptic cleft. -Mediate fast post-synaptic responses (induce rapid changes in membrane potential) -Neurotransmitter binds to ligand gated channel and we either have efflux or influx of ions depending on the receptor type. This current will change membrane potential -Occur point-to-point (local) meaning we go directly from the pre-synaptic to the post-synaptic membrane

study this M1 and M3 flowchart

-M1 and M3 activate Gq protein coupled receptor, which activates phospholipase C. The end result is increased intracellular calcium and increased protein kinase C activity. -M2 activates Gi protein coupled receptor, which leads to reduction in cAMP and protein kinase A (e.g. everything in heart goes down with M2 activation)

Where are M2 receptors abundant? What G protein are they coupled to and what effect are they related to?

-M2 receptors are abundant in the heart -They are also abundant on the presynaptic nerve terminals of the cholinergic (acetylcholine-producing) nerves -Coupled with Gi/o protein -Their activation leads to a decrease in cAMP and decreased PKA activity.

How does M3 receptor activation affect blood vessels?

-M3 receptors found on endothelial cells. Acetylcholine interacts with the M3 receptor, which stimulates calcium to enter the endothelial cell. -Calcium input will activate nitric oxide synthase, which produces NO from arginine. -NO diffuses into the vascular smooth muscle cells and activates soluble guanylate cyclase. This increases cGMP and will sequester Ca2+ inside smooth muscle cells. -Net result - relaxation of smooth muscle cells -So activation of M3 receptors on surface of endothelial cells will cause relaxation of the vasculature leading to control of vascular tone and blood pressure.

Explain multiple sclerosis. What system does it affect?

-MS is a *CNS* disease -A disease of demyelination, but also a disease with damage to the axons. This is because oligodendrocytes have multiple functions (like trophic support), not just myelination in the CNS. -Believed to be autoimmune

What is the role of magnesium in muscle contraction? What symptoms might someone with magnesium deficiency experience?

-Magnesium helps to facilitate the activity of the myosin ATPase and hydrolysis of ATP -Magnesium deficiency can cause muscle cramping or weakness. Often seen in people with GI disease, DM, alcoholism, or aging.

What is malignant hyperthermia? What causes it? How do you treat it?

-Malignant hyperthermia - genetic predisposition to be sensitive to volatile/inhaled anesthetics. Can cause ryanodine receptor to stay open in response to these drugs -Causes increased muscle tension and a BIG increase in heat production associated with this chronic muscle contraction -One way to treat this - use dantrolene - helps to prevent the chronic opening of ryanodine receptors on SR.

What is the Golgi tendon organ reflex?

-Mediated by Golgi tendon organs, which are found at the end of the muscle (in the tendon). This gives feedback to the brain to tell it how much tension a given muscle is generating. -Golgi tendon organs act as a protective "governor" for muscle by preventing development of excessive levels of tension, which could damage tissues. -This reflex is responsive to muscle tension (NOT MUSCLE STRETCH). -When you're actively generating tension (contracting a muscle), it activates these Golgi tendon organs and sends info back to the CNS, telling it how much tension the given muscle is generating.

What is SERCA? Why is it important?

-Membrane bound pumps = SERCA - a pump that pumps calcium from the cytosol back into the SR. It uses ATP to do this. -This is important in terminating contraction (as long as calcium is in cytoplasm, the crossbridge cycle will keep going. We don't want that).

What are metabotropic receptors? How do they work?

-Metabotropic receptors - G-protein coupled receptors on post-synaptic membrane -Receptor is NOT an ion channel. -Neurotransmitter binding to this receptor will activate the G-protein. G-protein's subunits will diffuse to activate its effectors. -Some of the G-protein effectors may be enzymes. Some may influence ion channels (thus influencing ion influx or efflux, which would also change membrane potential). -This process is relatively slow in causing changes in membrane potential when compared to the ligand gated ion receptors. This is because it takes multiple steps. -This process is diffusive because it involves G-protein diffusion and signal amplification.

Study this slide!! Review the Mnemonics to remember stuff.

-Mnemonics -top row - have a M&M AKA h-1, alpha-1, V-1, M1, M3. How does it work? Calcium, PKC through Gq) -second row - bigger, better deal at Hy-Vee AKA beta-1, beta-2, D1, H2, V2 -third row - mad 2 AKA M2, alpha-2, and D2. -fourth row - No messenger

What's the most important mechanism for removing Ca2+ from the cytoplasm to cause muscle relaxation? What's another, less important mechanism?

-Most important = re-uptake of Ca2+ into the sarcoplasmic retiulum by SERCA. -less important - membrane bound pumps that pump Ca2+ out of the cell and sodium-calcium exchangers found at cell membrane.

What initiates motor programs? Describe the path of motor programs.

-Motor cortex initiates motor programs -Motor programs travel through the brain and cross over, then go down the spinal cord via corticospinal pyramidal neurons. -These neurons then synapse with a motor neuron in ventral horn of the spinal cord -Motor neuron transmit signals to whatever muscle you're trying to activate

Explain synaptic transmission at the NMJ.

-Motor neuron fires an action potential, which propagates to the terminal. Membrane depolarization at the terminal opens the voltage gated Ca2+ channels, allowing Ca2+ to influx. Elevation of intracellular Ca2+ causes the release of vesicles -This releases neurotransmitter. In the NMJ, there is only one type of neurotransmitter = acetylcholine (this differs from the CNS!!!) -Once Ach is in the cleft, it will bind to its post-synaptic receptor. There is only one type of receptors for Ach - the nicotinic receptor (an ionotropic receptor). -This binding allows influx of Na+, which causes local depolarization of the membrane potential. If this is strong enough to reach the threshold, we'll have an action potential. The action potential will then propagate along the muscle fiber.

What is the motor end plate? What is the synaptic cleft?

-Motor neurons interface with the muscle fibers at a specialized neuromuscular junction, known as the motor end plate. -Motor end plate - axon and axon terminals of motor neuron and muscle fiber. -Synaptic cleft - gap between sarcolemma and axon terminal. -You can have one axon that innervates a lot of different muscle fibers

What is a motor unit? What is a motor pool? What is important to note about motor function?

-Motor unit - motor neuron cell body in spinal cord, motor axon (through ventral roots) and terminals, and muscle fibers innervated by a given axon and its terminals -Motor pool - all the motor units that activate a given muscle group or a given muscle -Motor function isn't all or nothing, meaning there are differing forces caused by graded muscle contractions (e.g. lifting up a tennis ball vs a bowling ball)

Explain how the number of muscle fibers innervated by a motor unit relates to their function in the body.

-Motor units that innervate a small number of muscle fibers are typically used for very fine movements (e.g. eye movements). -Motor units that innervate a large number of muscle fibers are typically used for powerful movements (e.g. quadricep innervation).

Osmosis - definition and trends

-Movement of water across a selectively permeable membrane -goes from area of high concentration of water (low concentration of osmotically active particles) to low concentration of water (high concentration of osmotically active particles)

What are the two main types of cholinergic (acetylcholine) receptors? Where are they found? What are the characteristics of the receptor?

-Muscarinic - on surface of many target organs of the parasympathetic system (eye, heart, bronchioles, pancreas, GI tract, bladder, etc.). A 7 pass transmembrane receptor and a G-protein coupled receptor. Has 5 subtypes (1 and 3 are very common, 2 is common in heart, 5 is commonly found in the brain). -Nicotinic - found in all ganglia. Not a transmembrane receptor. Actually a ligand gated ion channel. Sodium goes into cell and potassium leaves cell.

What causes muscular dystrophy? What are its consequences?

-Muscular dystrophy - caused by mutations in genes in dystrophin-glycoprotein complex -Costameres become disorganized -altered cell membrane integrity -inappropraiate Ca2+ leakage in cell -edema -inflammation -deposition of ECM

Are the sympathetic and parasympathetic divisions opponents? Give an example.

-No. You have many different types of receptors responding to different types of neurotransmitters from the two divisions of the autonomic nervous system (when one goes up the other goes down in order to modulate the function of the same organ. But they're not physiological opponents). In other words, they work on many different receptors to control the same organ. -e.g. the heart - beta-1 adrenergic receptors (sympathetic) and M2 receptors (parasympathetic). Activation of those two systems gives you the final different opposing actions. BUT the mechanisms are not antagonistic because they "come in through different doors."

Explain the process of mydriasis.

-Normal innervation in the eye - sphincter muscle is controlled by M3 receptors. Radial muscle is controlled by the alpha-1 receptor. -If you get into a dark room, alpha-1 receptor will be activated and will cause dilation of the pupil (mydriasis)

Explain information flow between neurons. Define synapse.

-Once an action potential reaches a terminal, it synapses with another neuron -Synapse = contacting point between the pre-synaptic site of the neuron generating the action potential and post-synaptic site of another neuron receiving the signal. In between is the synaptic cleft. -Synapses can be electrical or chemical. -Chemical synapses can be neuron-neuron or neuron-muscle

How does dopamine act as a reward signal, particularly in situations of cocaine addiction?

-Once dopamine is in the synaptic cleft, it can either bind to its post-synaptic receptor OR it can be transported back by the dopamine transporter to the pre-synaptic terminal. This maintains a low concentration of dopamine in the cleft. -Cocaine has a much higher affinity to bind with the dopamine transporter and hijacks this transporter. This leads to increased extracellular dopamine concentrations. -So... a much stronger stimulation is required to feel satisfied when on cocaine - to release dopamine and for the post-synaptic site to detect it (because receptors are saturated with dopamine from the cleft). -In the presence of cocaine, our system is not satisfied with conventional rewards. It is instead looking for cocaine.

What is the function of the slow negative cycle?

-Once membrane depolarization reaches a certain level, it will open K+ voltage-gated channels. K+ channels will initiate outward K+ current and hyperpolarize membrane. Much slower than other cycle.

What does increased stimulus intensity result in? What is one of the most important ways that we generate graded muscle contractions?

-Once you reach threshold (#3 on X-axis of graph), you start to recruit small motor units and produce a little bit of force. As stimulus intensity increases, you recruit more motor units, bigger motor units, and generate more force (until you reach the maximum). -One of the most important ways that we generate graded contractions is by progressive motor unit recruitment.

Where are beta-2 receptors abundant and what effects do they have on these organs?

-Present in blood vessels - causes vasodilation, which decreases total peripheral resistance, decreases diastolic blood pressure, and decreases afterload -Uterus - beta-2 receptor causes relaxation -Bronchioles - beta-2 receptor causes dilation. KNOW THIS ONE. -Skeletal muscle - beta-2 receptor increases glycogenolysis and causes contraction -Liver - beta-2 receptor increases glycogenolysis to increase blood glucose -Pancreas -beta-2 receptor increases insulin secretion

What nerves innervate the pupillary sphincter? What receptor is activated when you shine a light in the eye and what happens?

-Pupillary sphincter is richly innervated by parasympathetic fibers and related to M3 receptors -So whenever you shine a light into the eye, the M3 receptors are stimulated and you'll have constriction of the sphincter muscle. -This leads to miosis (pupillary constriction) because the accommodation will be different.

What is the function of the fast regenerative cycle?

-Quickly drives the membrane potential to the depolarized state -Due to the initial small depolarization -> opening of sodium channels -> inward Na+ current that will further depolarize the membrane potential and open more Na+ channels

What happens in the recovery phase of a chemical synapse?

-Recovery phase restores the system to its baseline level -This includes repolarization of the pre-synaptic membrane potential (K+ efflux through voltage gated K+ channels) and closing of voltage-gated Ca2+ channels. -Ca2+ ions are sequestered (removed from cytoplasm) to maintain homeostasis -vesicles are recycled (endocytosis)

What happens after a chemical synapse event?

-Remaining neurotransmitters are cleared up from the cleft -Need to also reduce the size of the pre-synaptic terminal because fusion of vesicles causes the membrane to increase in size. So these vesicle membranes will be recycled via endocytosis.

Define sarcomere, Z-disc, M-line/disc, A band, and I band.

-Repeating elements of myofibril = sarcomere -Boundaries of sarcomere = Z-disc (a structural element to act as an latching/anchoring point) -From one Z-disc to the next = sarcomere -M line/disc - a structural element in the middle of a sarcomere (serves as a latching on point) -Two types of bands - areas of myofibril where you either have thin filaments only (I band) or where you have a combination/overlap of thick and thin filaments (A band) -Light goes with I and dark goes with A

What effects does activation of the M2 receptor have on the SA node, AV node, atrial muscle, and ventricular muscle? Note that M2 is activated when the parasympathetic system is activated. What is the net effect of activating the parsympathetic system?

-SA node - decreased heart rate -AV node - decreased conduction velocity -atrial muscle - decreased atrial contraction -ventricular muscle - decreased ventricular contraction -Effects are stronger on AV node and SA node than on the ventricular and atrial muscle. -So when you activate the parasympathetic system, your heart rate/cardiac output goes down. This has a lot to do with M2 receptors.

What drugs block the norepinephrine transporter (NET)? What can be an effect of using these NET inhibitors?

-There are a number of drugs that block NET (e.g. cocaine and tricyclic anti-depressants). -These drugs cause the concentration of norepinephrine to increase in the synapse (so blood pressure can increase if you use a lot of these drugs).

What calcium source is essential to contraction of smooth muscle? How does this differ from skeletal muscle?

-There are calcium channels on cell membrane and calcium channels on sarcoplasmic reticulum. -In smooth muscle (unlike in skeletal muscle where basically all calcium comes from the sarcoplasmic reticulum), extracellular calcium is essential to its contraction.

What drug can block acetylcholine storage?

-Vesamicol blocks VAT. If you block VAT, the vesicles will be empty. This blunts the cholinergic response (when you need acetylcholine, you don't have it ready to go). -Not used as a real drug in practice, but you still need to know it for boards.

Contrast visceral and vascular smooth muscle.

-Visceral smooth muscle - varicosities of nerves can go directly on surface of cell or indirectly into the different layers of cells. Different ways of coupling (directly innervated, coupled, or indirectly coupled). -Vascular smooth muscle - less direct innervation. Direct innervation to outer surface only. Underneath vascular smooth muscle, you have an entire layer of endothelial cells that line the inner surface of all the blood vessels in our body. So vascular smooth muscle receives input from both direct innervation and the secretions of the endothelial cell layers.

What's the substitute for the motor end plate in smooth muscles?

-We don't have a motor end plate in smooth muscle. -We instead have a diffuse junction. This is where an autonomic nerve travels along a sheet of smooth muscle.

What is the alternative to an EPSP in the NMJ?

-We instead say end plate potential (EPP) because it's an end plate and not a post-synaptic neuron. -Muscle also has resting membrane potential, like everything. -nAchR channel opens from Ach binding. Influx of current depolarizes the skeletal muscle membrane. If this reaches threshold, an action potential is generated.

What happens to the ion gradient with each action potential cycle? How is this controlled? What's the role of ouabain?

-We lose a bit of the Na+ and K+ concentration gradient with each action potential cycle. -Controlled by Na+/K+ pump -Ouabain inhibits the Na+/K+ pump, which would SLOWLY deplete the concentration gradient. An axon will still be able to fire a bunch of action potentials during that time.

Voltage-gated Na+ channels

-activation and inactivation gates present and three states (two gates, three states) -closed state = at rest (hyperpolarized AKA more negative state) - activation gate closed, inactivation gate open -open state = when membrane depolarization is sensed by channel - activation gate opens. Inactivation gate still open. Na+ influx to follow its electrochemical gradient. -inactivation state = Inactivation gate closes in inactivated state. Activation gate still open. -return to closed state = ion channel returns to the closed state (activation gate closed, inactivation gate open) -needs to be in the C -> O -> I -> C order

What is the adrenal medulla? What neurotransmitters does it secrete? What is the mode of transport of these neurotransmitters?

-adrenal medulla = a huge autonomic ganglion that secretes the neurotransmitters (norepinephrine, dopamine, and peptides) straight into the bloodstream. These neurotransmitters then follow the bloodstream to the effector organs where they will interact with the receptors on the surface of these organs. -No post-ganglionic fiber -Neurotransmitter at the pre-synaptic ganglion is acetylcholine.

What are the catecholamines and their receptors? What factor do they share?

-all share a common biosynthetic pathway starting with tyrosine -dopamine (dopaminergic receptors) -norepinephrine (adrenergic/noradrenergic receptors - prefer alpha-adrenergic) -epinephrine (adrenergic/noradrenergic receptors - prefer beta-adrenergic)

What two adrenergic receptors are present in vasculature? What are their effects?

-alpha-1 (abundant - increases blood pressure) and beta-2 (decreases blood pressure) -this seems contradictory! We'll talk more on this later. But note now that the beta-2 receptors are more sensitive to catecholamines than alpha-1 receptors. So beta-2 will respond first, causing a slight decrease in blood pressure. But, as concentration of epinephrine and norepinephrine increases, alpha-1 will come into play and you'll have increased blood pressure. So, in summary, it depends on how much catecholamine you have in play.

Where are alpha-1 adrenergic receptors abundant? What happens if you activate those receptors in this locaiton? How can activation of this receptor be used therapeutically?

-alpha-1 adrenergic receptors are quite abundant in the vascular smooth muscle cells. -If you activate these receptors, blood pressure will increase. -Can activate this receptor to treat acute HYPOtension.

Explain the role of alpha-1 in the bladder

-alpha-1 in the bladder mainly controls the blood vessels and has little effect on the detrusor muscle. -alpha-1 has significant effect on trigone/internal sphincter -so when you activate alpha-1, you'll have urinary retention

Describe the structure and activation of the alpha-1 adrenergic receptor.

-alpha-1 receptor = a 7-pass transmembrane receptor -when agonist (epinephrine, norepinephrine, etc.) interacts with the receptor, the Gq protein comes in. Gq protein dissociation activates phospholipase C, which will facilitate the split of PIP2 to IP3 -As a result, you have an increase in intracellular Ca2+ (coming from stores and also activation of calcium pumps). -Increased calcium in vascular smooth muscle leads to vasoconstriction/contraction majorly. -DAG coming from this mechanism also activates protein kinase C with a lot of downstream effects through protein kinase C activation.

What receptors control the radial/dilator muscle of the eye? What effect does this have?

-alpha-1 receptors (sympathetic) -when you're scared, your pupil dilates.

What G protein are alpha-2 receptors coupled with? What happens when you activate these receptors?

-alpha-2 receptor is coupled with a Gi (inhibitory) protein. -alpha-2 and M2 are both inhibitory (easy to remember). -activation of alpha-2 receptors by binding of norepinephrine or epinephrine then activates Gi. -Gi's alpha subunit will then inhibit adenylyl cyclase. This will cause a decrease in cAMP and protein kinase A activity.

What drugs target NMJ's SNARE proteins?

C. botulinum and C. tetani.

Electroneutrality/net charge neutrality

Any macroscopic region of a solution (i.e. cytoplasm or extracellular fluid) must have equal number of positive and negative charges so that these solutions are electroneutral. -Note that only a very small relative number of excess charge is found on either side of the membrane, which gives us our membrane potential (i.e. membrane potential of -60 mV is only due to a very small number of excess charge). So, membrane potential is generated by an extremely small charge imbalance across the membrane - both sides thus maintain net charge neutrality.

What is autonomic integration?

Both parasympathetic and sympathetic nervous systems coordinate their functions.

What drug can block acetylcholine release?

Botulinum toxin - blocks activity of VAMP protein (so you won't release acetylcholine)

What drug inhibits catecholamine release? What condition can this drug treat?

Bretylium inhibits VAMP, which reduces vesicle fusion. Has been used to treat cardiac arrhythmia.

What are the primary neurotransmitters released for ANS and smooth muscle?

For ANS, the primary neurotransmitters released are acetylcholine and norepinephrine

Besides caveolae, what else is important to cell signaling in smooth muscle cells?

Gap junctions - facilitate cell-to-cell communication and are also important for cell signaling

Electrical driving force

Ions can generate electrical forces as they move down their concentration gradients. If a positive ion moves out of a cell, the cell's membrane potential becomes more negative. If a positive ion moves into a cell, the cell becomes less negative inside, etc. -Positive ions will be drawn into a cell by the electrical force whenever the membrane potential is negative. Negative ions will be pushed out of a cell by the electrical force whenever the membrane potential is negative.

What is saltatory conduction?

Conduction in presence of myelination

How is smooth muscle different from skeletal muscle, in general?

Differ in the way the contractile elements are arranged. Smooth muscle is not used in locomotion and is not attached to bone. Smooth muscle is typically found lining the walls of hollow organs.

Membrane potential - definition and requirements

Difference in electric potential between exterior and interior of a cell. -All cells have resting membrane potential. -Measured with an intracellular and extracellular electrode then using a voltmeter. -Convention = outside of the cell is at zero volts. Inside of cell at rest is always negative relative to the outside (so cell membrane potential = negative) -Requires uneven distribution of electrolytes -Charges or ions get separated via two mechanisms - active transport of ions through cell membrane and diffusion of ions through ion channels.

Nernst equation

E = RT/zF * ln ([ion out]/[ion in]) OR E = 61.5/z * log ([ion out]/[ion in]) assuming physiological temp Example: K+ where [K+]outside cell is 1 mM and [K+]inside cell is 10 mM. Ek = 61.5 log (1/10) = -61.5 mV. This number represents the potential needed to overcome equilibrium. Note that in the Nernst equation, it's all constants except two variables - concentration of ion out and concentration of ion in the cell. *THEREFORE, E represents the concentration gradient.*

Why is a fast EPSP only a transient disruption of membrane potential and not a sustained change in membrane potential?

Ligand gated receptors. If receptor is bound to ligand for longer time, it could lead to sustained effect on membrane potential. But it isn't. The ligand is only bound for a short time leading to a transient disruption of membrane potential. This is due to inactivation of the neurotransmitters.

What do the sensory organs of skeletal muscle contribute to?

Proprioception and protection of muscle from excessive stretch or strain

How do the potential outcomes of an NMJ differ from that of a CNS synapse?

NMJ only has excitatory effects and does NOT have inhibitory effects.

All-or-none rule

Once you reach action potential threshold, you generate an action potential. Increased stimulation doesn't give you a bigger action potential.

What's important to note about vesicle exocytosis vs endocytosis in chemical synapses?

It takes a much longer time to replenish/redock vesicles after stimulation than it does to exocytose vesicles in a chemical synapse event.

If extracellular K+ is increased from 4 mM to 40 mM, what will happen to membrane potential and why?

The membrane will be depolarized. The increase in extracellular K+ decreases the chemical driving force on K+ (because the gradient is less extreme) and thus there is less K+ leaking out. However, you still have the same amount of Na+ going in. The membrane is depolarized, which results in a new resting membrane potential (Vm). Another helpful way to view this is using the Nernst equation. Changing extracellular K+ from 4 to 40 causes Ek to change from -95 to -33.5 mV (less negative).

How do smooth muscle cells respond when there are low levels of calcium inside the sarcoplasmic reticulum?

Sometimes if you get particularly low levels of calcium inside the sarcoplasmic reticulum, channels can form that funnel calcium from the extracellular fluid into the sarcoplasmic reticulum.

What is the neurotransmitter used presynaptically (i.e. prior to the ganglion)?

The neurotransmitter used is acetylcholine (i.e. all the synapses at the ganglion are cholinergic). This applies to both sympathetic and parasympathetic divisions of the ANS

Why are airways and blood vessels able to always hold a certain level of tone?

This is able to occur because the energy demand is much lower in smooth muscle than in skeletal muscle.

GLUT1 transporter kinetics

Transport rate depends on -glucose concentration gradient -transporter number (more transporters = higher Vmax. e.g. insulin increases number of GLUT1 transporters in cell membrane) -affinity of glucose binding to transporter (recall Km = concentration at 1/2*Vmax. Higher Km means lower affinity of GLUT1 for glucose - so higher concentration of glucose is required to reach Vmax.)

What are the key regulatory proteins that regulate access to the active site on the actin thin filament?

Tropomyosin governs access to active site on the actin thin filament.

What are the key regulatory protein(s) that confer calcium sensitivity in skeletal muscle?

Troponin C in troponin complex, which is attached to tropomyosin.

What is the calcium sensor in skeletal muscle?

Troponin, specifically troponin C

Which type of muscle fibers tends to be recruited first?

Type I fibers tend to be smaller and therefore (as mentioned earlier) tend to be recruited first

The majority of the synapses in the brain and PNS are __________ synapses.

chemical

Equilibrium potential, E, is measured in millivolts, but indicates the strength of the _________ driving force.

chemical E is measured in mV, but really represents the concentration gradient. E also represents the potential needed to overcome equilibrium.

Where is the myogenic response most pronounced?

arterioles

Voltage gated Na+ channel blocker

tetrodotoxin from pufferfish

the costamere is a _________ element, which links __________________ to ______________.

the costamere is a structural element, which links actin filaments to basal lamina

Why is low dose dopamine used to treat patients with low urine output as a result of decreased cardiac function (i.e. heart failure patients)?

dopamine causes increased glomerular filtration rate, increased renal blood flow, and increased sodium excretion

What is the lipid bilayer permeable to in simple diffusion? What is it impermeable to?

gases and small uncharged polar molecules - due to hydrophobic core of bilayer. -Things like water soluble molecules, water, and ions CANNOT move through the bilayer via simple diffusion. They need protein transporters.

Length constant for excitable membranes/axons

lambda = distance between the injection site and the point where the steady state voltage change has decayed by 63% from its peak state (37% of voltage magnitude remains). Measured by injecting current at position 0. Current injection produces a voltage response. If you measure voltage with electrodes further down the axon, you can see how fast voltage response decays over distance. -The bigger the length constant, the better. This applies to passive conduction because there is decay over distance.

Describe the way in which smooth muscle cells contract

Smooth muscle cell contraction - cells shrink and screw up in a corkscrew-like fashion

What is acetylcholine's receptor? Where is this neurotransmitter dominant?

-Nicotinic receptor = fast ionotropic receptor of NMJ -Muscarinic receptor = slower metabotropic receptor with G-protein association -NMJ of skeletal muscle motor neurons, ANS, CNS

What makes the adrenal medulla special?

-No ganglionic synapse prior to it. It is directly innervated. -Neurotransmitter is acetylcholine, which then stimulates the release of norepinephrine and epinephrine into the bloodstream.

What neurotransmitter do most of the postganglionic fibers of the parasympathetic division of the ANS secrete? What are their receptors called?

-majority secrete acetylcholine. -receptors are called muscarinic receptors.

What are the homotropic receptors of note?

-presynaptic adrenergic (norepi, epi) auto-receptor = alpha-2 -presynaptic cholinergic (Ach) autoreceptor = M2 Note that both end in 2 = inhibitory.

What happens in rigor mortis?

If you don't have ATP present, the myosin head will not let go and stays bound to actin (explains rigor mortis in death - no more ATP, so actin-myosin crosslinking is stuck like that). Muscles are super tense.

The preganglionic fibers (thoracolumbar system/adrenal medulla for sympathetic and then the cranial/sacral outflow of the parasympathetic) all secrete what neurotransmitter? What receptors are present on ganglia to respond to this neurotransmitter?

-Acetylcholine!!! -Nicotinic receptors (for acetylcholine) are present on ganglia to respond to acetylcholine secreted from these pre-ganglionic nerve fibers.

A 51-year-old female experienced frequent "attacks" when her heart raced and pounded; she had a throbbing headache and visual disturbances; she felt hot, but her hands and feet were cold. The family doctor thought these were menopausal symptoms and prescribed hormone replacement therapy over the phone. The medication did not relieve the symptoms. -Office visit & labs: -Vitals: BP 200/110, HR 120 bpm, 24-hr urinary 3-methoxy-4-hydroxymandelic acid (VMA) positive -CT scan: 3-cm mass on the right adrenal gland -Dx: pheochromocytoma (a tumor that secretes a lot of catecholamines in the body) Medications: phenoxybenzamine (alpha-1 adrenergic antagonist) propranolol (beta adrenergic antagonist) after phenoxybenzamine dose was established Surgery: remove tumor -1 - Explain what effects the medications will have. -2 -Explain the symptoms based on the diagnosis. What receptors are involved? -3 - Why did the patient feel hot while feet and hands were cold

-1 - -phenoxybenzamine - an alpha-1 adrenergic receptor antagonist. Recall that alpha-1 receptors are abundant in vasculature. So if you block alpha-1, you decrease total peripheral resistance and, therefore, blood pressure. Beta-2 can't win against alpha-1 when there's this high amount of catecholamines -Propranolol is a nonspecific beta receptor antagonist (blocks beta 1 and 2 receptors). Beta-1 receptors are also activated by catecholamines. These receptors are abundant in the heart. So blocking the beta receptors would prevent catecholamines from binding and thus would prevent blood pressure from rising. -2 - receptors involved - alpha-1 and beta-1. Heart rate is increased because of beta-1 adrenergic receptor activation. -3 - cold hands and feet - vasoconstriction of arterioles in skin of extremities

What are the 3 mechanisms for inactivating neurotransmitters on the ligand binding receptors?

-1 - Diffusion - neurotransmitters are small molecules and can diffuse away from the synaptic site. This is a natural way to decrease the concentration of neurotransmitter/lead to its inactivation -2-Enzymatic degradation - Enzymes in cleft can degrade the neurotransmitter -3-Transport mechanism - transport neurotransmitter back to pre-synaptic terminal OR to astrocytes by the synaptic cleft. Astrocytes are a type of glial cell.

What are two causes of glaucoma?

-1 - increase in production of aqueous humor by the ciliary body epithelium causes the pressure in the anterior chamber to build up. -2 - Blockage of canal of Schlemm also causes increased pressure of anterior chamber and thus glaucoma.

What are the 3 different modes of innervation of the sympathetic division?

-1 - preganglionic neuron originates from neuron cell bodies, goes to the paravertebral ganglia or prevertebral ganglia, and synapses with the post-ganglionic neuron, which then goes to the organ (long preganglionic fiber, shorter postganglionic fiber, leading in to organ). Note that the sympathetic fibers emerge from T1 to L3, but the chain of sympathetic ganglia extends from the upper part of the neck to the coccyx where the left and right sympathetic chains merge in the midline and form the coccygeal ganglion. -2 - preganglionic neuron originates from neuron cell bodies and goes to specialized ganglia before it synapses with post-ganglionic fibers that go to a target organ. -3 - adrenal medulla - no post-ganglionic fibers. Pre-ganglionic neuron goes straight to the organ. Secretes substance from preganglionic neuron into the bloodstream, which then goes to the target organ

Generation of action potential - a series of highly elaborate events leading to a time course of voltage changes

-1 - resting state - NON-voltage-gated Na+ and K+ channels are open to maintain/create the resting membrane potential. Voltage-gated Na+ and K+ channels are closed. -2 - A little depolarization - activates some of the voltage-gated Na+ channels. Na+ ions will influx (this is driven by the concentration gradient and electrical driving force). -3 - Positive ion influx (Na+) will further depolarize the membrane potential. This further depolarization will open more Na+ voltage-gated channels (positive feedback). This quickly depolarizes the membrane. -4 - Na+ voltage-gated channels will become inactivated. K+ voltage-gated channels were unopened this whole time, but they will now become activated/open due to the high membrane depolarization. K+ ions efflux. These two actions work in concert to bring the membrane potential back to the level of step 1. -5 - Membrane potential undershoots and becomes even more hyperpolarized because of prolonged opening of K+ channels (both non-voltage gated to reset membrane potential and voltage gated). Voltage-gated K+ channels will close due to hyperpolarization, which returns us to step 1.

What are the two reasons why energy demand (ATP demand) is much lower in smooth muscle than in skeletal muscle?

-1 - speed of the cross bridge cycle is much slower in smooth muscle relative to other muscle types (see figure). The isoform of myosin ATPase in smooth muscle is different than the isoform for skeletal muscle. The smooth muscle isoform cycles more slowly because it takes longer to detach, even when phosphorylated. For a given amount of time, if you do fewer cycles, and thus you use less ATP. -2 - latch state - where you can stop the cross bridge cycle in the middle.

What are the two constellations of axons of the parasympathetic division of the ANS?

-1st group = cranial outflow -has preganglionic fibers that follow the oculomotor nerve (CN III), facial nerve (CN VII), glossopharyngeal nerve (CN IX), and vagus nerve (X). Vagus nerve is special because it innervates many different organs (whereas the other cranial nerves listed in this paragraph only do one or a few). Ganglia lie scattered in close relation to the target organs. -2nd group = sacral outflow - from S3-S4. Emerge from spinal cord, synapse in a group of scattered pelvic ganglia (interestingly contains sympathetic and parasympathetic fibers), and have short postganglionic fibers that run to target tissues.

Where are N-nicotinic receptors found? What effect does activation of this receptor type have in each location?

-Adrenal medulla - have an N-nicotinic receptor. Activation of that receptor causes secretion of epinephrine and norepinephrine, which then increases blood pressure -In autonomic ganglia - have N-nicotinic receptors everywhere. Net effect depends on parasympathetic vs. sympathetic innervation and dominance in the particular organs.

What would happen if you used a drug that blocked muscarinic receptors on sweat glands?

If you use a drug that blocks muscarinic receptors, the body temperature will increase A LOT.

What is the SNARE complex? How does it work?

-A group of proteins that mediate vesicle docking and fusion = SNARE complex -SNARE complex are cytosolic and transmembrane proteins (both vesicle membrane and plasma membrane) -When Ca2+ concentration is increased, the SNARE complex has a protein that senses it and activates the complex. The complex brings the vesicle closer to the plasma membrane for fusion to take place.

Explain Eaton-Lambert syndrome

-A presynaptic disease caused by antibody production against voltage gated Ca2+ channels. -This usually takes place in cancer patients and is auto-immune. -Less Ca2+ entry to presynaptic terminal reduces Ach release at the NMJ and thus causes muscle weakness.

What is the sarcoplasmic reticulum? What is its function? What is a triad?

-A reticular network called the sarcoplasmic reticulum runs next to T tubule network. Sarcoplasmic reticulum is a specialized form of ER in muscle cells -One of its many purposes = reservoir for calcium -Outpouchings at edges of sarcoplasmic reticulum are known as the terminal cisternae or junctional sarcoplasmic reticulum -2 terminal cisternae of sarcoplasmic reticulum + 1 T-tubule = triad

Primary active transport - ABC transporters and clinical relevance

-ABC protein superfamily -bind ATP in the "cassette" (hence ABC) -CFTR receptor is part of this family. Acts as a chloride channel. Channel opening/closing is controlled by ATP binding. Mutation = cystic fibrosis, which causes abnormal transport of chloride and sodium across the epithelium. Leads to thick, viscous secretion in lungs, pancreas, liver, and intestines. -MRD-proteins (multi drug resistance) are part of this family and export stuff from cytosol to the extracellular space. Cause resistance to cancer drug therapy when overexpressed in tumors. Transport cancer drug out of cell before drug can kill cell.

What regulates access to the active site on the actin molecule? What molecule is required to initiate the contraction process?

-Access to the active site is regulated by a protein complex = Troponin complex of troponin T, C, and I -Ca2+ triggers contraction of skeletal muscle by interacting with troponin C

What is the use for acetylcholinesterase inhibitors?

-Acetylcholine accumulates in synatic cleft and increases all of the functions downstream from the synapse (in the target organ). -e.g. farming -e.g. treatment of CNS conditions where you have disbalance between cholinergic and dopaminergic systems in brain -e.g. glaucoma - aqueous humor synthesis -e.g. terrorists using an organophosphate to block this enzyme and cause lots of neurological/bronchial dysfunction

How do intermediate filaments link adjacent myofibrils?

-All of the different myofibrils are attached together at the Z disc by the intermediate filaments -In other words, intermediate filaments attach adjacent myofibrils together

What does the cranial outflow innervate? What happens if you have damage to cranial nerves of the cranial outflow? Given an example where there's a tumor compressing CN III.

-CN III = eye (pupillary constrictor and ciliary muscle at ciliary ganglion) -CN VII = salivary glands (submaxillary and sublingual at submaxillary ganglion) and nasopharynx (lacrimal and nasal glands at sphenopalatine ganglion) -CN IX = parotid gland at otic ganglion -CN X = thoracic and abdominal viscera (heart, lungs, stomach, liver, pancreas, spleen, small intestine, colon) -If you have damage to those cranial nerves, you can also affect the parasympathetic division in the cranial outflow as well. -Parasympathetic fibers controlling the ciliary muscles and pupillary sphincters travel within the oculomotor nerve. So, a tumor compressing CN III not only affects the muscle movement of the eye, but also the autonomic response of the pupillary muscles. This is an example of how somatic function disorders can also affect autonomic function.

How can calcium released within the smooth muscle cell help to modulate the membrane potential on the outer part of the cell? Why is this important?

-Calcium can act on channels that conduct potassium (calcium activated potassium channels) or it can act on calcium activated chloride channels. -This is important because this also affects the voltage gated calcium channels on the cell membrane.

What ion channels does protein kinase A affect in the SA node of the heart? What would activation of the M2 receptor cause?

-Calcium channels are super important to SA node. So you have less calcium available with protein kinase A inhibition -The potassium channel, which changes the membrane potential, is also inhibited when protein kinase A is inhibited. This also contributes to a decrease in heart tissue actions through hyperpolarization. -Voltage-dependent opening of sodium current channels is shifted to more negative (hyperpolarized) potentials -Activation of the M2 receptor (because of the activation of the parasympathetic system) causes everything in the heart to be suppressed.

Explain calmodulin's role in smooth muscle contraction.

-Calmodulin is involved in a lot of different signaling pathways. -When you have an increase in calcium in the smooth muscle cell, calmodulin binds that calcium. -Calmodulin then goes on to activate myosin light chain kinase -Myosin light chain kinase then goes on to phosphorylate the regulatory light chain on the myosin head/neck (recall that the neck/hinge region on the myosin molecule has a regulatory light chain and an essential light chain. These are really important in smooth muscle). -Phosphorylation of regulatory light chain is the permissive step in the initiation of smooth muscle contraction -The cross-bridge cycle can begin.

How are Duchenne MD, Becker MD, and Limb-Girdle MD different?

-Can have mutations in different parts of dystrophin-glycoprotein complex or integrins. Results in different disease states. -Duchenne MD - no dystrophin expression at all (dystrophin is absent). One of the most severe types - often fatal by early 30s/late 20s as a result of respiratory failure -Becker muscular dystrophy - dystrophin levels reduced, but still present. Less serious form. Typically doesn't result in death. -Limb-girdle dystrophies - associated with mutations in the genes coding for the sarcoglycans or other components of the dystrophin-glycoprotein complex.

Describe the process of adrenergic neurotransmission. Include catecholamine synthesis, storage, release, and termination of action.

-Catecholamine synthesis: starts with transport of tyrosine into nerve body. Then you have tyrosine converted into DOPA by tyrosine hydroxylase. DOPA is then converted to dopamine. -Catecholamine storage: Dopamine gets put in vesicle via VMAT. Once in the vesicle, dopamine is further converted into norepinephrine. So dopamine, norepinephrine, and ATP are all present in the vesicle. -Catecholamine release: same mechanism as acetylcholine release. Depolarization of membrane with voltage changes opening voltage gated sodium channels. This activates voltage gated calcium channels. Calcium channels will increase calcium in the nerve terminal. Calcium binds to calmodulin. Calcium-calmodulin complex causes VAMP to start working. VAMP causes fusion of vesicle to the membrane of the nerve terminal. Norepinephrine, ATP, and P are released into the synaptic cleft. -Catecholamine termination of action - 3 outcomes: 1) norepinephrine goes to the target organ to act on its receptors. 2) Norepinephrine diffuses in synapse region, then travels back to nerve terminal. It re-enters the nerve terminal via an auto-receptor. Once the auto-receptors are activated, the norepinephrine synthesis and secretion pathway will be inhibited. 3) norepinephrine can be directly taken back up into the nerve terminal via the norepinephrine transporter (NET). This is a very important pathway.

How can you diagnose hypocalcemia?

-Chvostek's sign - tap muscle in front of ear, which will induce a contraction in hypocalcemia. However, this test is not very sensitive or specific for hypocalcemia (regular people can have it and not every hypocalcemic person has it) -Trousseau's sign - a good test (both sensitive and specific). Put a blood pressure cuff on patient and will cause muscle spasm of hand and forearm.

What happens to the ciliary muscle if you activate the M3 receptor? What condition can be treated by activation of this system?

-Ciliary muscle is also related to M3 receptors -If you activate the M3 receptor, it brings the ciliary muscles closer together. This, in combination with the constriction of the pupillary sphincter, causes some angle (I don't understand what angle) to become bigger. This causes the lens to puff up. -As a result, you have spasm of accommodation (AKA near vision). -When this angle gets bigger, there is easier drainage of aqueous humor. So, we can stimulate this system to treat glaucoma (by increasing the angle).

If E(Cl-) is more negative than the resting membrane potential, what will happen when the inhibitory neurotransmitter GABA opens ligand-gated Cl- channels?

-Cl- ions will influx, resulting in membrane hyperpolarization. See figure. -For Cl-, electrical driving force is represented by the black arrow. The chemical driving force is the seafoam green arrow. These two forces act on Cl- in opposite directions (chemical driving force causing influx, electrical driving force wanting Cl- to efflux to bring potential closer to 0). The chemical driving force is bigger, so the overall movement of Cl- is influx. This produces a small membrane hyperpolarization.

What are the names for fibers that secrete norepinephrine, dopamine, and acetylcholine, respectively?

-If a fiber secretes norepinephrine, it is called adrenergic. -If a fiber secretes dopamine, it is called dopaminergic. -If a fiber secretes acetylcholine, it is called cholinergic.

How does myelination increase velocity/propagation? What is myelin composed of?

-Decreases membrane capacitance, meaning it takes less current to charge the membrane and more current can flow forward. Recall that capacitance is the ability to store charge, so decreased capacitance makes it so charge is more likely to move forward. -Also increases membrane resistance to prevent current leakage out of the cell where myelination is present. -Net effect = makes sure most of the current (if not all) will move forward to the next spot to generate action potential -Myelin is composed of cholesterol, other lipids, and proteins

Describe the structure of a diffuse junction and what happens when it is depolarized.

-Diffuse junctions have multiple outpouchings, called varicosities, that are filled with vesicles of neurotransmitter. -As an action potential travels along an autonomic nerve, it depolarizes it. This causes calcium influx from extracellular fluid and release of neurotransmitter from varicosities into the area outside of the varicosities. -There's not really a synaptic cleft in diffuse junctions. -Neurotransmitters are released into the diffuse junction and spread around, going into the surrounding smooth muscle cells

After a chemical synapse event, how is calcium sequestered and removed? (Recall we have very low intracellular calcium levels)

-Diffusion: Because Ca2+ channels are localized at the terminal site and influx of Ca2+ ions will only increase Ca2+ locally, we can restore the concentration by just having Ca2+ ions diffuse in other parts of the cell. -Ca2+ binding proteins bind free Ca2+, which also serves to decrease the intracellular Ca2+ concentration. -Ca2+ ions can be transported into internal Ca2+ stores, like in the ER. -Ca2+ ions can be pumped out in channels (like Na+/Ca2+ exchanger).

Duchenne muscular dystrophy is associated with a genetic mutation that affects expression of which protein? How is expression affected?

-Dystrophin -In Duchenne MD, dystrophin is completely absent

What is the dystrophin-glycoprotein complex? What are its functions? What happens if there are mutations in the proteins of this complex?

-Dystrophin-glycoprotein complex = spans cell membrane and goes into basal lamina -Actin thin filament attaches to dystrophin. Dystrophin is therefore the link between the contractile elements inside the muscle cell and the complex of proteins that reaches across the cell membrane into the basal lamina (basement membrane). Like a scaffolding. -Confers structural integrity to muscle cells and acts as scaffolding for myofibrils. -Mechanical coupling between muscle cell and basement membrane will be messed up by a mutation in any of these proteins -Dystrophin can be poorly expressed in various types of muscular dystrophy

Compare the effects of M3 activation with intact and damaged endothelium.

-Effects of M3 activation on intact endothelial cells leads to the production of endothelium-derived relaxing factors (EDRFs) like nitric oxide. This results in vasodilation. -People with damage to the endothelial cell layer of vasculature can disrupt the mechanism described above. When you lose this mechanism, *acetylcholine will bypass the endothelial cell layer* and no EDRFs (like NO) are produced. Acetylcholine instead goes straight to M3 receptors that are also found on smooth muscle cells. -This then increases Ca2+ in smooth muscle cells and we have contraction (instead of relaxation!). So this damage can lead to increased blood pressure

Besides progressive motor unit recruitment, what is one of the most important ways to produce graded muscle contractions? Include definitions of unfused tetanus and complete tetanus.

-Frequency summation -We stimulate one motor unit and keep turning up the stimulus frequency. At low frequency, we get a given amount of force from the single motor unit. -If we turn up the frequency of stimulation, we get progressively greater force production from the same motor unit. This is known as *unfused tetanus* (progressive increase in muscle tension generated in response to repeated stimuli). You see a stairstep progression to maximal force development because there are progressive increases in the levels of calcium in the cytoplasm of the muscle cell. Each time you stimulate the cell, calcium gets released and then starts to be re-sequestered. But if the stimulus is frequent enough, the calcium never gets completely taken away and you get progressively higher levels of calcium in the muscle cell (and as a result - progressively higher levels of force generation for a given muscle cell) -If we turn up the stimulus frequency even more, we have very high action potential frequency in a single motor unit. We now have maximal sustained force production from this single motor unit (known as a complete tetanus). This looks like a plateaued graph of muscle force. This is because maximal calcium levels are reached.

Explain fast inhibitory post-synaptic responses mediated by GABA binding to ionotropic receptors. Define inhibitory postsynaptic potential (IPSP).

-GABA receptors are localized on the post-synaptic membrane -Binding of GABA activates this ligand gated ion channel (ionotropic). -These receptors are chloride channels. Opening of this channel allows Cl- to influx. -Influx of negatively charged ions causes the post-synaptic membrane potential to be hyperpolarized. -This brings the post-synaptic cell AWAY from the threshold for firing an action potential -This is IPSP - membrane potential brought AWAY from action potential firing threshold. -IPSP is a local potential, meaning it has decremental spread.

What is Gauer's sign?

-Gauer's sign - a way to diagnose MD by looking at how a child gets up from a prone position -Kids with MD have to use arms to get up from a prone position because of weakness in legs and hips

After norepinephrine is taken back up into the nerve terminal by NET, what can happen?

-Gets re-packed into a vesicle for storage -Can be degraded by MAO. This is where people on MAOIs come into trouble with the tyramine pathway. Excess tyramine/norepinephrine isn't degraded and blood pressure can rise.

Explain how glutamate binding to an ionotropic receptor can cause an excitatory post-synaptic potential (EPSP at a glutamatergic synapse with ionotropic receptors). Define EPSP.

-Glutamate is released into the synaptic cleft and diffuses to bind to its receptor on the post-synaptic membrane. -Binding of glutamate to the glutamate receptor activates the ion channel. In this case, K+ leaves and Na+ enters. The channel is more permeable to Na+, so the net effect is Na+ influx, leading to membrane depolarization. This will bring the membrane potential closer to the action potential threshold. -The response of the post-synaptic membrane to any actions that bring the membrane potential closer to its threshold for action potential = excitatory postsynaptic potential (EPSP). -EPSP increases the likelihood of action potential generation because it's bringing membrane potential closer to threshold.

Explain Guillain-Barre syndrome. What system does it affect?

-Guillain-Barre syndrome is a *PNS* disease. -Believed to be auto-immune - where antibodies mistakenly attack PNS and cause demyelination -Muscle weakness/paralysis -PNS can re-generate myelination so recovery is possible

Describe innervation in the gut.

-Gut is innervated by ANS, but also has intrinsic innervation (enteric nervous system - the brain in the gut). Intrinsic innervation affects smooth muscle tone in the gut. -Gut is able to sense signals (mechanical or chemical) within the lumen. The afferents (at) are integrated within the gut and can affect efferent (exit) neural output (smooth muscle tone/peristalsis or secretion of hormones/ enzymes/ chemical/ etc.). -Capable of receiving, integrating, and sending signals without CNS input.

Give an example of activation of the stretch reflex.

-Hammer testing of reflexes on knee activates stretch reflex -Patellar tendon pulls on quadriceps muscle. Applying a force to the patellar tendon (via the hammer) activates the stretch reflex and tells the quadriceps muscle to contract in order to help alleviate some of this stretch.

What happens in hypokalemia? What is its impact on the membrane potential of cells? How do you treat hypokalemia?

-Have decreased extracellular K+ and muscle weakness -hyperpolarization of cells' resting membrane potential -give K+ IV

What happens in hyperkalemia?

-Have increased extracellular K+ -Cells' resting membrane potential is disrupted (depolarized). -Leads to abnormal function of muscles, heart, and nerves.

How do the Golgi tendon reflex and stretch reflex work together? Give an example where you're holding a balloon vs a bowling ball in your hand and flexing your arm.

-Holding two different objects (balloon and bowling ball) and flexing your arm. This generates tension in your bicep and is stretching your triceps muscle -Measuring from Golgi tendon organs in biceps and muscle spindles in triceps. -In balloon situation - you're not having to generate much tension in your bicep to support balloon weight. Golgi tendon organs are thus firing at a relatively low frequency (because you're not generating much muscle tension). You also have a given muscle length for your triceps muscle (a given action potential frequency that corresponds to that muscle length). As you raise your arm up, you're stretching the triceps so it's at a different muscle length (the muscle spindles are firing more rapidly due to the stretch reflex (indicating the change in that muscle length)). When you lift a balloon, there's not much change in muscle tension - so there's not much difference in Golgi tendon organ firing (they don't fire). -When you're holding a bowling ball - you have to generate a lot more tension. This causes action potential frequency in Golgi tendon organ to be much higher than that of the balloon example. Muscle spindle action potential frequency (AKA stretch reflex) will be the same as the balloon example because you're at the same triceps length. As you raise your arm up, the muscle spindles fire. You may also have a slight increase in the action potential frequency of the Golgi tendon organ. -In summary - both Golgi tendon organ and muscle spindles (stretch reflex) fire in bowling ball example. The Golgi tendon organ doesn't really fire at all in the balloon example (not really any load), whereas the muscle spindles do fire with flexion.

What happens to the A and I bands in muscle contraction?

-I band shrinks -A band doesn't change

Explain the mechanism of muscle excitation by a motor neuron.

-Impulse travels down a motor neuron axon and goes to its respective axon terminal and motor end plate. -Once the impulse reaches the end plate, there's a sequence of events: -Wave of depolarization travels down axon and reaches axon terminal. This causes opening of voltage gated calcium channels at the axon terminal. -Subsequent calcium influx into axon terminal. This causes fusion of vesicles within axon terminal with the cell membrane. Vesicles are full of acetylcholine and release acetylcholine into the synaptic cleft when they fuse with the membrane of the axon terminal. -Acetylcholine travels across synaptic cleft and binds to receptors on the post-synaptic membrane (motor end plate). These receptors are ligand gated ion channels (ligand = acetylcholine). Binding of acetylcholine causes a conformational change, channel opens, and allows for influx/conductance of sodium ions (also minor K+ efflux). -Subsequent depolarization of post-synaptic membrane - this is NOT the action potential that's transmitted in the muscle. This is instead an end plate potential -End plate potential travels on and causes opening of voltage gated sodium channels. THIS is when you have generation of an action potential in a muscle cell itself.

What are the different neurotransmitters used post-ganglionically (i.e. at the level of the tissue)?

-In some cases they're still cholinergic (AKA acetylcholine (e.g. parasympathetic division to heart and vessels). -The sympathetic division of the ANS releases norepinephrine to the alpha and beta adrenergic receptors. -In the skin - we have sweat glands and vessels. Although it is sympathetic, we have acetylcholine and cholinergic receptors. -In the kidneys - we have sympathetic nerves releasing dopamine and norepinephrine. -Uncertainty about importance of dopamine release from sympathetic nerves of kidney

What effect do M3 receptors have in the bladder? What would too much M3 stimulation cause there?

-In the bladder, the M3 receptor (parasympathetic innervation) causes contraction of the detrusor muscle. It also causes peristaltic urethral contraction and inhibits (releases) the external sphincter. -This allows urination to happen -Too much stimulation = voiding, urinary incontinence

What metabolizes norepinephrine in the bloodstream?

-In the bloodstream, norepinephrine is metabolized by COMT.

Where are dopaminergic receptors abundant and what effects do they have on these organs? What are the different dopaminergic receptor types?

-In the dopaminergic receptor activation, we have D1 and D2 receptors. -we have a lot of D1 receptors in vasculature (renal, mesenteric, coronary). You activate the dopamine receptor, which causes vasodilation and thus increased glomerular filtration rate, increased renal blood flow, and increased sodium excretion.

Describe how saltatory conduction works.

-In the figure, there's a stimulation causing membrane depolarization at point A. This depolarization will drive Na+ channels into an open state and subsequently into the fast regenerative cycle (including an AP if threshold reached). -Current moves forward due to insulation from myelination. Current reaches next node (point B) of Ranvier and causes membrane depolarization there. If that reaches its threshold, it results in an action potential. -"Jumps" (sorry, Dr. Lindgren) from point A to B -Current will move forward and backward, but there's still the absolute refractory period, so it doesn't do anything when going backward. *-Action potentials are only generated in the nodes of Ranvier* -Conduction is fast because you aren't wasting time generating action potentials in the membrane covered by myelin and because the membrane capacitance is much lower than in an unmyelinated nerve. -Conduction is energy efficient because less membrane generates action potentials. This means there is less Na+ flowing in to the cell and there is less work for the Na+/K+ pumps. -Speed still also depends on axon diameter

What effect do M1 receptors have in the gut?

-In the gut, M1 receptors stimulate increased secretion of glands in GI tract.

What is the predominant adrenergic receptor in the heart? What is the runner-up and in what clinical situations is it relevant?

-In the heart - we have a lot of beta-1 adrenergic (85%) receptors, but we also have alpha-1 (15%) receptors. -So alpha-1 doesn't contribute much to the contraction of the heart. -EXCEPT in heart failure - decreased abundance of beta-1 receptors, while the abundance of alpha-1 stays the same. So alpha-1 becomes important.

How can EPSPs reach the action potential threshold?

-Individual EPSPs are very small, so we need several of them to reach the action potential threshold in the post-synaptic cell. EPSPs can layer over one another and reach the threshold. -Summation of EPSPs takes place at the initial segment/hillock of the axon (layered both in space and in time - called spatial and temporal summation). -When the initial segment becomes sufficiently depolarized, voltage-gated sodium channels open and an action potential is generated.

What gives skeletal muscle its striped appearance?

-Individual myofibrils are made of thick and thin filaments -Thick and thin filaments are arranged in series and in a repeated fashion -This gives skeletal muscle a striated (striped) appearance

What is found within the calcium release unit and what is their function?

-Inside of the calcium release unit in the SR - have specialized proteins called calsequestrin and calreticulin that act as calcium buffers. Calsequestrin and calreticulin bind up calcium inside the SR (concentration of free calcium inside the SR is pretty low because these specialized buffers have bound it all up) -They bind up the calcium and hold it next to the door where calcium will be released (so it's ready to go!)

What are integrins? What is a costamere? What happens if there is a mutation in genes encoding a component of the costamere?

-Integrins - membrane spanning proteins. Attach indirectly to Z discs. Play a similar role to dystrophin (as a structural element that links cytoskeleton with extracellular matrix). -Combination of integrins and dystrophin-glycoprotein complex create the costamere. Costameres almost always center on the Z disc -A costamere is the link between contractile elements inside the cell and the anchoring point outside the cell. -Mutations in costamere proteins = bad (like muscular dystrophy)

What broader category do chemical synapses belong to? What else belongs to this family?

-Intercellular chemical signaling -Other family members = -Neurohormones - substance released into bloodstream by a neuron -Neurotransmitters - distributed locally (AKA paracrine) by diffusion, which then goes to several nearby cells. OR Distributed by diffusion once they are released by pre-synaptic terminals and have a nearby post-synaptic site (mediating point-to-point transmission). Most localized transmission in this category.

Explain the cause, symptoms, diagnosis, and potential treatment of myasthenia gravis.

-Myasthenia gravis is a postsynaptic disease caused by autoimmune responses to the nicotinic Ach receptors. -Antibodies are generated against Ach receptors (hence, postsynaptic). -In myasthenia gravis, there are fewer functional Ach receptors. There is no way to acutely increase the number of functional Ach receptors. They do still have some Ach receptors that still exist. -Symptoms in early stage = patient is okay in the early morning, but develops diplopia and slurred speech as the day progresses. Patient will have facial muscle weakness (ptosis and smile weakness) and weakness in general. -Diagnosis - give the patient edrophonium, which is an acetylcholinesterase blocker. If symptoms improve, the patient probably has myasthenia gravis. -We can treat this condition using neostigmine, a reversible acetylcholinesterase inhibitor. This leads to a reduction in Ach degradation. So Ach will hang out in the cleft for a longer period of time. This indirectly enhances the function of existing Ach receptors. This drug causes Ach to be presented for a longer period of time to the existing Ach receptors.

What can cause mydriasis? How can you test the response to light in these two cases?

-Mydriasis can be caused by activating alpha-1 or inhibiting M3 -response to light will be different in these two cases -If you shine a light in the eye and see pupil constriction, then you know M3 is ok. -If you shine a light in the eye and don't see pupillary constriction, then M3 may be inhibited

What opposes the actions of myosin light chain kinase and causes relaxation of smooth muscle? What affects the activity of this enzyme?

-Myosin light chain phosphatase opposes the actions of myosin light chain kinase by dephosphorylating the regulatory light chain on the myosin head/neck. -Constantly active. Activity is modulated by hormones, neurotransmitters, etc.

Explain the structure of an individual myosin molecule. What is the function of each part?

-Myosin molecule has 2 chains wrapped around each other -Two heavy chains wrapped in an alpha helix -Globular head portion - one head per chain -On neck/hinge portion (between tail and head) - light chains present. There is an essential and regulatory light chain, which are important for regulation of muscle function - both for skeletal muscle and smooth muscle -Neck/hinge region allows myosin heads to move -Myosin heads moving is really what produces muscle force. -Red arrow is pointing out how each myosin head has enzymatic activity. Able to hydrolyze ATP and utilize this energy to produce movement of the myosin head -Myosin ATPase is very important to muscle function

What is a neuromuscular junction (NMJ)? What are its components and how do these differ from the CNS synapses?

-NMJ - one motor neuron innervates one skeletal muscle. These two form a motor unit. There are multiple nerve terminals on one muscle fiber. -Axon myelination goes all the way to the terminal -Junctional folds act as the post-synaptic membrane. -Motor end plate - post-synaptic site that contains the junctional folds -Active zones - multiple zones in the presynaptic nerve terminal where vesicles are clustered. These clustered areas are specialized sites for releasing the neurotransmitter acetylcholine. In CNS there's just one active zone per synapse, but there are multiple active zones in the NMJ. -Only one neurotransmitter in NMJ - acetylcholine. -Only one type of receptor - nicotinic acetylcholine receptor.

What are some unconventional neurotransmitters and why are they considered unconventional?

-NO - a gas (not put in vesicles) produced by nitric oxide synthase, which is regulated by Ca2+ binding to calmodulin. -endocannabinoids - produced by enzymatic degradation of membrane lipids. e.g. anandamide, 2-AG, and THC. Bind to CB1 and CB2 receptors. -adenosine - all vesicles contain ATP that is co-released with other transmitters. Once ATP is outside the cell, enzymes will degrade it into adenosine. Adenosine then binds to purinergic receptors.

How can losing endothelial cell surface lead to blood clots?

-NO is an EDRF that is important in anti-thrombosis -So losing endothelial cell surface leads to blood clots, etc.

What factors influence action potential threshold?

-Na+ channels -K+ channels -[Ca2+] outside the cell

Describe conductance changes of Na+ and K+ channels when membrane potential is suddenly depolarized for 2 msec.

-Na+ channels open (activated) and then close (inactivated) before the 2 msec is over -K+ channels only open (activate) during this period of time. The rate of opening of K+ channels is much slower than that of Na+ channels.

Trends in membrane potential

-Na+ higher in extracellular fluid than intracellular fluid (142 out vs 10 in) -K+ higher in intracellular fluid than extracellular fluid (4 out vs 140 in) -Ca2+ significantly higher in extracellular fluid than intracellular fluid (2.4 out vs 0.0001 in) -Cl- significantly higher in extracellular fluid than intracellular fluid (103 out vs 4 in)

Besides MLCP, what else causes smooth muscle relaxation?

-Need to pump calcium out of cytoplasm of smooth muscle cell. -Calcium is pumped out via membrane bound pumps (like the sodium/calcium exchanger) or into the sarcoplasmic reticulum by the SERCA pump (which uses ATP).

What can regulate smooth muscle excitation and inhibition?

-Neural (neurotransmitters from nerve cells that innervate smooth muscle in close proximity). Nerves release neurotransmitters at diffuse junctions that can then go on and bind their receptor. This then causes a change in intracellular Ca2+ levels. -Hormones circulating in blood that can act on receptors in caveolae and help to modulate the excitatory state of smooth muscle -Paracrine agents - agents produced by cells that are in close apposition to smooth muscle. e.g. blood vessels - endothelium also releases substances (paracrine agents) that can alter the excitatory state of smooth muscle

Where are M-nicotinic receptors found? What effect does activation of this receptor type have in this location? What effect would an antibody or drug that blocks this receptor have?

-Neuromuscular junction - have M-nicotinic receptors. -Stimulation leads to twitch/hyperactivity of skeletal muscle. -Antibody or drugs blocking these binding sites leads to muscle paralysis

Define neurotransmitter vs neuromodulator.

-Neurotransmitter - substance that acts on the target receptors to cause a specific action -Neuromodulator - substance that controls the secretion of another neurotransmitter (e.g. neuropeptide-Y, which is a huge treatment method for obesity)

Explain the muscle contraction cross bridge cycle

-Once you've pulled tropomyosin out of the active site on actin, you can go through the cross bridge cycle - this is where force is generated. -Myosin head has ATPase, so the head likes to bind ATP. If ATP is available, it will bind in a pocket in myosin (panel 1 of figure). -This process causes a conformational change in the myosin and dissociation between the myosin head and the actin filament. In other words, the start of the cross bridge cycle is ATP causing dissociation between actin and myosin head (panel 2 of figure). -Hydrolysis of ATP to ADP and Pi then occurs in ATPase of myosin head. Energy that comes from this hydrolysis of ATP causes another conformational change of the myosin head and the myosin head cocks back (panel 3 of figure). -Once the myosin head is cocked, it is ready to pull the actin filament towards the center of the sarcomere. As long as the active sites are exposed and calcium is present, then myosin will bind to actin filament (panel 4). -Inorganic phosphate is released (after ATP hydrolysis) (part of panel 5). -Power stroke - there's another conformational change of the myosin head, in which the myosin head ratchets and pulls the actin filament towards the center of the sarcomere (panel 5). -ADP is released (panel 6). -Then if ATP is present, it will bind and the cycle will repeat (panel 1).

What is one way that we regulate the amount of muscle force that we produce? Explain how this works.

-One of the ways that we regulate the amount of muscle force that we produce = recruit motor units in a given order -Those motor units are distinct -This means that the motor units recruited first are going to produce the smallest amount of force. The motor units recruited at the very end (with the highest stimulus intensity) are going to produce the greatest amount of force

Explain how arterial pressure is controlled through the autonomic feedback loop as an example of how the integration of the sympathetic and parasympathetic systems works in the cardiovascular systems.

-Our blood pressure is the product of total peripheral resistance and cardiac output. -Cardiac output is the product of heart rate and stroke volume (If you decrease heart rate or stroke volume, you decrease blood pressure (where beta-1 adrenergic receptors and M2 receptors come in play)). -Total peripheral resistance is mainly controlled by alpha-1 adrenergic receptors. -If you activate the sympathetic system, you have alpha-1 increase TPR and beta-1 increasing cardiac output - both controlling blood pressure. If you block those factors, you would decrease blood pressure. -If you increase blood pressure, this stimulates an increase in baroreceptor discharge (baroreceptors are abundant in the aortic arch and carotid sinus). This increase in impulses will act on the vasomotor center, which works on both the sympathetic and parasympathetic divisions. -The vasomotor center acts on the sympathetic system first. There is a decrease in sympathetic tone (sympathetic tone means the synthesis and secretion of neurotransmitter - so in this case there is decreased norepinephrine and epinephrine). Decreased sympathetic tone causes a decrease in vasoconstriction and, at the same time, a decrease in cardiac contraction and heart rate. This is because there is less norepinephrine, so beta-1 and alpha-1 are not stimulated as much. These things will act to bring blood pressure down. -The vasomotor center then acts on the parasympathetic system to activate the vagal tone. If you activate the vagal tone, you increase secretion of acetylcholine. Acetylcholine goes to the M2 receptor in the heart, which does the opposite of beta-1's function when beta-1 is active. This means M2 results in slower heart rate and less contractility. -This, in combination with the decrease in sympathetic tone, will bring down the heart rate, cardiac contraction, and vasoconstriction with a net result of decreased blood pressure. -Our body automatically does the above process in response to an ACUTE increase in blood pressure. So, if you do something to increase blood pressure, you expect to see a drop in heart rate. This is called reflex bradycardia.

How is the autonomic feedback loop controlling arterial blood pressure affected in patients with hypertension?

-Our body automatically does this process in response to an ACUTE increase in blood pressure. So, if you do something to increase blood pressure, you expect to see a drop in heart rate. This is called reflex bradycardia. In patients with hypertension, this process doesn't really go down because they've adapted over a long period of time.

What is myelination caused by in the PNS and CNS?

-PNS = Schwann cell that myelinates one axon bundle (like wrapping a scarf around one neck) -CNS = oligodendrocyte that myelinates multiple axon bundles (like multiple arms giving out multiple hugs to axons)

Contrast axon length in parasympathetic vs sympathetic divisions of the ANS

-Parasympathetic - long pre-ganglionic fiber, then it synapses at a ganglion, and sends off a short post-ganglionic fiber into the effector organ. So typically the effector organs lie close to the ganglion. -Sympathetic - shorter pre-ganglionic fiber and longer post-ganglionic fiber leading in to the effector organ.

What are the different neurotransmitters in the sympathetic and parsympathetic systems?

-Parasympathetic - neurotransmitter secreted at the ganglion and at the effector organ is acetylcholine -Sympathetic - neurotransmitter at the ganglion is acetylcholine. Neurotransmitter at the effector organ is norepinephrine (the key neurotransmitter in the sympathetic nervous system).

Why would you not want to give agents that stimulate M3 receptors to patients with obstructive lung disease? What would treatment with M3 receptor inhibitors do for these patients?

-Patients with obstructive lung disease (asthma, COPD) have a lot of bronchoconstriction. So you don't want to treat them with agents that stimulate M3 receptors because M3 causes contraction, bronchospasm, and secretions. -However, if you treat these patient with M3 receptor inhibitors, you could cause bronchodilation. So this could be used to treat asthma, etc.

Endocytosis - definition and types

-Plasma membrane invaginates to form a vesicle that brings stuff into the cell -phagocytosis (macrophages, neutrophils) -pinocytosis (cell drinking done by all cells) -fluid-phase endocytosis (uptake of materials dissolved in extracellular fluid. Materials not bound to receptors. VERY inefficient because of low specificity and because most target substances are in low concentration in ECF) -receptor-mediated endocytosis (can concentrate specific receptor proteins at site for endocytosis) -caveolae endocytosis (like clathrin, but uses caveolae and caveolin as coating protein. Caveolae are well-defined invaginations in the plasma membrane. Can be a special type of lipid raft).

Explain sympathetic outflow and sensory pathway.

-Sympathetic outflow - Impulse leaves nerve body and follows the ventral root. Impulse goes to a ganglion before it goes to the target organ. -Sensory pathway - has visceral receptors and follows back the other way, ending up in the dorsal horn.

Explain the differences in the metabolisms of small-molecule neurotransmitters vs peptide neurotransmitters.

-Small molecules neurotransmitters - synthesized and packed in vesicles at nerve terminals. Released to then bind their receptors. *Small clear-core* vesicles (how they appear under electron microscopy). -Peptide neurotransmitters - peptide precursor must be synthesized in nucleus (because they're proteins) and then packed into *large dense-core* vesicles. They're then transported down the microtubule tracts to the presynaptic terminals. This is very different from the small molecule neurotransmitters. Peptide neurotransmitters require more Ca2+ for their release.

Compare and contrast the following between smooth and skeletal muscle - nuclei number, filaments involved/filament arrangement, and anchoring elements.

-Smooth muscle cells only have one nucleus (unlike skeletal muscle cells that are multinucleated) -Smooth muscle cells have the same thick and thin (myosin and actin, respectively) filaments as skeletal muscle -The way these filaments are arranged, however, is different than skeletal muscle. In smooth muscle, these filaments are kind of arranged all over the place. This contributes to the non-striated appearance of smooth muscle. -Smooth muscle cells do not have Z disks. They have dense bodies (in cytoplasm) and dense plaques (in cell membrane) - these are similar to Z disks - act as anchoring points for actin filaments. So when the actin filaments produce force, it affects the overall cell.

What neurotransmitter does the somatic system secrete? What are its receptors called?

-Somatic system = one single axon from spinal cord to target -acetylcholine secreted and nicotinic receptors on target organ

Describe unidirectional action potential propagation.

-Starting from the beginning - If there's enough membrane depolarization in the hillock/initial segment to reach the AP threshold, then the membrane depolarization will activate Na+ channels and an action potential will be generated. -Positive current will propagate forward and will depolarize neighboring membrane. This membrane depolarization will again depolarize Na+ channels. If threshold is reached in this patch, then an action potential will be generated there. -This also creates current that travels to the neighboring patch and so on and so on. -It feels like action potential is being propagated from one place to another. But really, action potential is being generated in discrete patches of membrane. -Note that the currents are also moving backwards! (This just happens naturally). However, we don't have re-excitation and we don't have generation of an action potential of the previous patch due to the absolute refractory period (Na+ channels are inactivated).

Explain motor unit recruitment in the example where we have small, medium, and large motor units

-Stimulator is hooked up and stimulating 3 different motor units (3 cell bodies in ventral horn of spinal cord). These motor units are different sizes (small, medium, and large) and they're all innervating the same muscle. -Stimulating at different frequencies. -At low action potential frequency/stimulus intensity - recruits the smallest motor unit first. Generates a relatively small force (in relation to the muscle's capacity). -At moderate action potential frequency/stimulus - recruit the first and the second (small and medium) motor units. The amount of force that you're generating increases - moderate amount. -At near maximal action potential frequency/stimulus - recruit all the motor units and get near maximal force produced.

What encodes stimulus intensity?

-Stimulus intensity is encoded in the nervous system by *frequency* of action potential. -Action potentials are "all or nothing." So.... The stronger the stimulus, the closer together the action potentials are going to be (the higher the frequency they're going to fire at). -Recall the relative refractory period - you need a stronger stimulus to get an action potential to fire -A sustained stimulus gives you the third chunk of the figure.

What are the different ways you can regenerate ATP for muscle contraction?

-Store of creatine phosphate - allows us to re-phosphorylate ATP relatively quickly. Very finite amount of this. Doesn't support muscle contraction for very long (so only for short term muscle activity). -anaerobic and aerobic glycolysis -beta-oxidation -The different muscle fiber types rely on anaerobic vs aerobic pathways

What is the muscle stretch reflex?

-Stretch reflex = single synapse reflex that is sensitive to stretch of a muscle (whatever a given muscle length is, it sends info back to the CNS. This gives feedback on how much the muscle is stretched). -These reflexes are important for proprioception and also prevent over-stretching or over-activation of muscle.

What mediates the stretch reflex? How does this work when you stretch a muscle and when you make a muscle slack?

-Stretch reflex is mediated by muscle spindles, which are composed of intrafusal muscle fibers and are specialized fibers within the muscle that contribute to proprioception. -Note that normal muscle fibers = extrafusal muscle fibers -When you stretch muscle spindles, they send info back to the spinal cord and brain that tell it "hey, the muscle is being stretched to this length." As you stretch a muscle, you see an increase in generation of action potentials from the intrafusal muscle fibers. -If you make a muscle slack, you see a decrease in the number of action potentials.

Describe inputs to the vascular smooth muscle and the underlying endothelial cells.

-Sympathetic nerve fibers secrete norepinephrine into the vascular smooth muscle. Vascular smooth muscle also receives input from sensory-motor nerves. -In the underlying endothelial cells, we have shear stress stimulating this level all the time. Endothelial cells receive all the inputs coming to the vasculature via the blood. Endothelial cells secrete chemicals like NO, etc. that then diffuse into the smooth muscle.

Describe the process of cholinergic neurotransmission. Include synthesis, storage, release, and termination of action.

-Synthesis of acetylcholine: Choline and sodium uptake through a choline transporter (CHT) (symport). After choline uptake, choline is conjugated together with acetylCo-A to make acetylcholine. This is controlled by choline acetyltransferase. (ChAT) -Acetylcholine storage: Acetylcholine will be taken up into vesicles using the vesicle associated transporter (VAT). We need vesicles of acetylcholine so we always have acetylcholine ready to go. -Acetylcholine release: Depolarization of nerve terminal by voltage gated Na+ channels (Na+ influx). Membrane potential change (AKA depolarization) activates voltage dependent calcium channel. Calcium influx to cytosol. Calcium forms a complex with calmodulin, which activates the vesicle associated membrane protein (VAMP). In other words, VAMP binds with calmodulin-calcium in order to be activated. Activated VAMP causes vesicles to fuse with synaptic membrane and release acetylcholine (via exocytosis). -Acetylcholine termination: Has 3 possible routes. 1) acetylcholine goes to target organs in close proximity of synapse. 2) TERMINATION = acetylcholine is rapidly hydrolyzed by acetylcholinesterase into choline and acetate. Choline can then follow the extracellular fluid to re-enter the cholinergic transmission cycle. 3) acetylcholine can go right back into the presynaptic neuron and act on an auto-receptor. This decreases the cAMP concentration in the cytosol of the pre-synaptic terminal. This is a negative feedback mechanism.

What structure of muscle cells helps to transmit the action potential? Describe this process, including a description of L-type receptors.

-T tubules help us to transmit the action potential. Action potential goes down the T tubules and into the muscle cell. -Action potential ends up in triad = junction of sarcoplasmic reticulum (x2 terminal cisternae) and T tubule. -Once at the triad - wave of depolarization triggers conformational change in voltage sensors found in the membrane of the T tubules. These voltage sensors are ion channels = L-type calcium channels (AKA dihydropyridine receptors). -Conformational change of L-type receptor does 2 things: *Main thing* = L-type receptor alters the conformation of a channel found in the sarcoplasmic reticulum (so L-type calcium channel is mechanically coupled to another receptor). This channel in the sarcoplasmic reticulum membrane is a calcium release channel known as a ryanodine receptor. Ryanodine receptor allows Ca2+ to flow OUT from within the sarcoplasmic reticulum and into the cytoplasm of the cell. This initiates the cross bridge cycle. *Second thing* - L-type calcium channel isn't always coupled to a ryanodine receptor. Conformational change of the L-type calcium channel can allow Ca2+ to flow into the cell from extracellular fluid (not as big of a role). -So, calcium can enter the cytoplasm from the sarcoplasmic reticulum and/or the extracellular fluid. BUT in skeletal muscle, the most important source of calcium is in the sarcoplasmic reticulum

How does tetanus toxin target NMJ SNARE proteins? How does it differ from botulinum toxin's effects?

-Tetanus toxin targets SNARE proteins. -Behaviorally, it produces muscular tetanic contraction. This contrasts with botulism, which causes muscle weakness. -The difference lies in the different neurons targeted. -Motor neurons (botulism) directly control muscles. -In the spinal cord, we also have inter-neurons (tetanus), which are inhibitory neurons that use GABA and glycine to inhibit motor neurons. So, breaking down the SNARE complex in the inhibitory terminals weakens the inhibitory drive in the spinal cord. This will DISinhibit the motor neuron and induce hyperexcitation of the motor neuron.

Explain how hormonal and autonomic feedback loops work together to control mean arterial pressure. What is the meeting point of these two loops?

-The figure shows how the autonomic feedback loop and the hormonal feedback loop work together to control mean arterial blood pressure. -NOTE - the mean arterial pressure is the key stimulus and the meeting point - it goes one way or the other - it triggers the two systems in opposite ways to try to bring it back to the previous value. -When you use drugs that change the mean arterial pressure, you should expect the reflex mechanisms as a result.

What are the 3 ways to increase calcium in smooth muscle?

-The first two come from outside the cell - calcium comes from extracellular fluid through a membrane bound channel. -1 - Channel can be opened by depolarization of cell membrane (causes a conformational change in a voltage gated L-type calcium channel. Opening of channel allows passage of extracellular calcium into cytoplasm). -2 - Channel can be opened by binding of a ligand (ligand binds to receptor on cell membrane, causes a conformational change in the channel, opening of channel allows passage of extracellular calcium into cytoplasm). -The third comes from within the cell -3 - Second messenger system - neurotransmitter or hormone that binds to its receptor on the surface of the cell and then has a G protein coupled receptor. -IP3 is second messenger, for example. IP3 travels from cell membrane and binds to its receptor on the sarcoplasmic reticulum membrane. That receptor then opens and allows calcium to diffuse out from the sarcoplasmic reticulum and into the cytoplasm of the cell.

Define action potential threshold

-The lowest voltage or minimal depolarization to required to drive Na+ channels into the fast, regenerative/positive feedback loop. -Once reaching the threshold, action potential generation no longer depends on stimulation.

Explain how post-synaptic responses by metabotropic receptors differs from those of ionotropic receptors.

-The metabotropic receptors can also produce post-synaptic responses, but these are slow. -This process is much slower than the fast EPSP or IPSP. -Also note that metabotropic receptors do not always link to ionic channels. When they do, they decrease or increase conduction through chloride or potassium channels. -The activation of the metabotropic receptors do not always produce a membrane potential change. They could instead influence the signaling cascade in the post-synaptic sites.

Where do the nerve bodies that give rise to the axons of the sympathetic division of the ANS lie?

-The nerve bodies that give rise to the axons of the sympathetic nervous system come from the intermediolateral cell column of the lateral horn from T1-L3. -AKA Thoraco-lumbar division

What is synaptic delay? Why does this happen? What can synaptic delay tell you about postsynaptic receptor type?

-The pause between the arrival of an action potential in the presynaptic terminal and the onset of a potential change in the postsynaptic cell. -Delay is due to all the events that collectively lead to activation of post-synaptic channels. This includes fusion of synaptic vesicles with presynaptic membrane, diffusion of transmitter across synaptic cleft, and activation of postsynaptic channels. -Synaptic delay can tell you if you have an ionotropic or metabotropic postsynaptic receptor because delay will be fast for ionotropic and much longer for metabotropic.

What are the multiple conditions required for summation of EPSPs to take place?

-There are many different conditions required in order for summation to take place -First chunk of the figure - the neuron can receive multiple impulses at the same location (as well as inhibitory inputs). E1 site can be stimulated twice and each time induces an EPSP. But the interval between them is too long. So, we reach baseline between the two stimulations at E1, meaning there's no layering. -Second chunk of the figure - time interval shortened between E1's two stimulations. The second stimulation at E1 rides on top of the first. This helps the second stimulation to reach the firing threshold and induce an action potential. -Third chunk of the figure - we stimulate at two different locations, E1 and E2. This leads to spatial summation (helping to reach the action potential threshold) if E1 and E2 are stimulated simultaneously. -Fourth chunk of the figure - if we stimulate E1 at the same time as an inhibitory input, we see shunting (?) mechanisms. -After spatial and temporal stimulation, there's only 3 states the neuron will be driven to: resting, excited, and inhibited.

Explain the structure of the thick filament.

-Thick filaments are made of a bunch of myosin molecules -Myosin is a bipolar molecule -Filaments are wrapped together in a helical fashion -Myosin heads are arranged in a radial array (so not just arranged above or below, like some 2D photos show) -Myosin heads interact with actin filaments

Explain the structure of the thin filament.

-Thin filament = F-actin, which is made up of actin subunits. Actin subunits are bound together and twisted into a helix. -Each actin molecule has an active site - where myosin head binds to actin filament. Need myosin head and actin to interact to produce force

What is denervation supersensitivity AKA withdrawal rebound hyperactivity (most common usage) AKA disuse hyperactivity?

-This is the idea that if you cut a nerve, after some time you will cause the downstream structure that is innervated from that nerve to be super-sensitive (much more sensitive to neurotransmitter than normal). -Another application - if you keep blocking ganglionic transmission or block the postsynaptic receptors, then the target organ will become super-sensitive when you remove that blocker.

What is the mechanism of nicotinic receptor activation?

-This receptor is an ion channel!! -Two alpha subunits house binding site for acetylcholine -When you activate these two subunits, the subunits will open and sodium will go into the cell and potassium will go out of the cell.

What are the functions of titin? What does it attach to?

-Titin attaches at center of sarcomere by the M line and goes all the way out to the Z disc. -Attaches at circled part on the left of the figure and goes to the thick filament (myosin) -Binds everything together -Titin also functions to provide some elasticity/resistance to stretch as muscle expands -e.g. generation of muscle tension during lengthening contractions (e.g. quads while walking down stairs) - titin may be activated by calcium and interact with actin filament near Z disc

Explain what happens when an action potential is initiated at a hillock and propagates to the terminal in chemical synapses.

-Transmitter packed into vesicles and vesicles docked, ready to go. -Membrane depolarization will open the voltage gated calcium channels located in the pre-synaptic terminal -Recall that there's a huge concentration gradient of calcium ions (extracellular much higher than intracellular). This results in calcium influx, increasing intracellular calcium concentration (locally). -This initiates exocytosis of the neurotransmitter vesicles -Vesicle contents released into synaptic cleft. -Neurotransmitters in cleft passively diffuse to the post-synaptic site -Neurotransmitters bind to their receptors that are concentrated on the post-synaptic terminal -This activates these ligand-gated ion channel receptors. Influx or efflux of certain ions occurs, which changes the post-synaptic membrane potential. -If that change brings the membrane potential closer to the action potential threshold, that increases the likelihood an action potential will fire post-synaptically.

Secondary active transport

-Transport of a substance against its concentration gradient, coupled with the downhill movement of another substance (rather than a metabolic process) -can be antiport or symport, but one substance must be moving down its electrochemical gradient -energy lost by substance moving down its gradient is captured and used to transport the other substance against its gradient -most co-transporters use inward movement of sodium to drive inward movement of another substance. Some also use the outward movement of potassium to drive the outward movement of another substance. -sodium is also used as an energy source for exchangers (antiport)

Explain the relationship between troponin and tropomyosin.

-Troponin is attached to the tropomyosin helix/rope. When you don't want muscle contraction to occur, tropomyosin sits on top of active site and blocks it (so you can't have the actin/myosin head interaction) -When Ca2+ influx occurs, Ca2+ binds to troponin C. This causes a conformational change in TnC, which pulls on tropomyosin. Tropomyosin is yanked out of the actin active site and myosin head can interact with active site. -Tropomyosin (red line) is also regulatory - helical/rope-like structure

A child has a dilated pupil that does not respond to light on his right side. What could be the potential causes? What did we learn the cause was in class?

-Tumor affecting right side (ANS travels in same nerve as oculomotor cranial nerve). -Head injury. -Problem with parasympathetics. -Drugs. -Actual cause: he played with a flower and then rubbed his right eye. These flowers contain a blocker of M3 receptors. -If he ate it - that would cause a "wet picture"

What drug inhibits catecholamine storage? What effect will this have on blood pressure? Why?

-VMAT is blocked by reserpine. -If you use reserpine (actually used as a drug!), your blood pressure will drop. This is because you blocked the production/storage of norepinephrine. Used to be a HTN treatment. Not used as much, but sometimes needed for severe cases.

Describe M2 receptor activation at the SA node of the heart.

-Vagus nerve varicosity = where acetylcholine is secreted. -M2 cholinergic receptor found in post-synaptic membrane. This receptor is associated with the G protein of the inhibitory/olfactory subtype (Gi/o) -So when the M2 receptor is activated by acetylcholine, the alpha subunit dissociates from the G protein and then goes on to inhibit adenylyl cyclase. -This inhibition of adenylyl cyclase leads to a decrease in cAMP and thus a subsequent decrease in protein kinase A activity. -Finally, as a result, you have a lot of inhibition of ion channels in heart

Explain how arterial pressure is controlled through the hormonal feedback loop.

-When blood pressure drops acutely, you end up with decreased renal blood flow. This leads to increased renin production and increased angiotensin and aldosterone. -Increased aldosterone increases sodium and water retention, which causes increased blood volume and cardiac output. -Increased cardiac output contributes to increased blood pressure. -At the same time, you have increased sympathetic drive in response to the drop in blood pressure through the baroreceptor mechanism. This increased sympathetic drive contributes to an increase in total peripheral resistance, which also increases blood pressure. -Note that angiotensin will lead to an increase in angiotensin-II, which is a very strong vasoactive substance that also increases total peripheral resistance. -Hormonal mechanisms takes longer than the autonomic feedback loop. But both mechanisms occur at the same time and work together to control mean arterial pressure.

Explain the relationship between velocity, axoplasmic conductance, membrane capacitance, and axon radius/diameter.

-When you have a larger current, the current will also leak out of the membrane more. -The velocity is proportional to the axoplasmic conductance, which is proportional to pi*r(squared). -The velocity is inversely proportional to the membrane capacitance, which is proportional to 1/(2 ** pi ** r). This is because the capacitance determines how much current you will lose. -Note that electrical conductance increases faster than the capacitance increases (this is because one plot is squared and the other is linear). -Increasing axon diameter increases the speed of conduction

Give an example of a sensory reflex in skeletal muscle.

-When you touch a really hot or cold surface you get immediate activation of a motor neuron (nociception in skin - receptors in skin send a signal back to the spinal cord via the dorsal root. These signals synapse with an interneuron and then send a signal right back out through the ventral root. Motor neuron activates a skeletal muscle and you pull your hand away).

What drugs can you use to treat increased intraocular pressure or glaucoma? Why?

-You can use beta blockers to treat high intraocular pressure and glaucoma. -beta-1 and beta-2 receptors control the ciliary body epithelium. These two receptors, when activated, will stimulate the production of aqueous humor. An increased production of aqueous humor can cause glaucoma or increased IOP.

What is a tetrad? What is a tetrad paired to and what is this pairing called?

-You typically have a grouping of the L-type calcium channels in the T-tubule. This is referred to as the tetrad. -Tetrad is paired to a ryanodine receptor in SR membrane. Combination of tetrad and ryanodine receptor = "calcium release unit"

Why do you want to keep muscle spindles relatively taut? What contributes to their tautness?

-You want them to stay relatively taut so they are very sensitive to any change in length. -You control this using efferent fibers (gamma motor neurons innervate muscle spindles and keep them relatively taut. Efferent fibers detect any small change in length).

What happens if you block M3 in the pupillary sphincter muscle and then shine a light in the eye? What could cause M3 dysfunction?

-You would not have constriction of the pupil. -So, for e.g., if a patient has difficulty adjusting to bright lights, it suggests they have something affecting muscarinic function in the eye. -This could be from an autonomic disorder or some drug that blocks muscarinic function (or tumors in both eyes, which would be crazy lol) -If it's just difficulty adjusting in one eye, this could be from a tumor compressing a cranial nerve and affecting the parasympathetics that are hitching a ride on that cranial nerve.

Explain the structure of the Z disc? What two major things attach to it? What are its functions?

-Z disc - lattice-like structure (see upper right hand corner of this slide) -Two things that attach/anchor to Z disc = actin (thin) filaments and titin filaments -many other functions besides anchoring (like signaling, regulation of muscle development, etc.).

What is pharmacomechanical coupling?

-a hormone or neuroreceptor or drug that binds to the cell surface and doesn't affect the membrane potential at all. However, through a second messenger signaling system, it can affect the excitatory state and, therefore, the contraction/relaxation of that smooth muscle. -i.e. they alter force production independent of membrane potential

What is the relative refractory period? What is the significance of the relative refractory period?

-a second stimulation during this period would cause a response in the neuron. But this comes at a greater cost because you either need to increase the strength or duration of the stimulation. -Stronger stimulation required due to K+ channel's prolonged opening -Sets up the upper limit of firing frequency -Ensures unidirectional propagation of the action potential

What is the absolute refractory period?

-a second stimulation during this period would not cause a change in the action potential or response in the neuron (no matter how intense the stimulus is) -Due to Na+ channel activation and inactivation (most are inactivated)

What is a desmosome? What is its important to smooth muscle cells?

-a specialized structure that facilitates cell-to-cell adhesion (how smooth muscles in a sheet stick to each other)

How can smooth muscle be damaged in disease? Give an example.

-accumulation of cellular debris from epithelial damage and airway inflammation -submucosal thickening by edema and infiltration -smooth muscle contraction, hyperplasia, and hypertrophy. -Asthma is a reactive airway disease that leads to bronchoconstriction from some irritant -Asthma can eventually cause smooth muscle hypertrophy (increased muscle size)

Besides amino acids, what else can act as small molecule neurotransmitters?

-acetylcholine -biogenic amines like histamine and the monoamines (serotonin; catecholamines (dopamine, norepinephrine, epinephrine)) -purines

What will happen to heart rate if you give patients an acetylcholinesterase inhibitor?

-acetylcholine will accumulate and heart rate will go down.

Say you have a cell with just sodium and potassium. The cell membrane is permeable to both K+ and Na+. Na+ extracellular is 142 and intracellular is 10. K+ extracellular is 4 and intracellular is 140. What happens?

-although the membrane is permeable to both K+ and Na+, it is permeable to these ions at a different level (it is more permeable to K+ because there are more K+ channels expressed in a cell). -Vrest sits between Ek and Ena, but closer to Ek. -resting membrane potential (Vrest) is primarily determined by K+ channels and K+ concentration gradient across membrane. Na+ channels play a minor role. -at rest, there is no net ion flux across the membrane (there is still movement, just not overall) -constant K+ efflux is counter-balanced by constant Na+ influx. -Since there is constant K+ efflux and constant Na+ influx, you may worry the gradient would run out. Na+/K+ pumps restore ion concentration gradients, maintaining a higher concentration of K+ inside the cell and a lower concentration of Na+ inside the cell. These pumps move Na+ and K+ against their gradients to restore the gradient (i.e. the pumps move Na+ out and K+ in)

Where are alpha-1 receptors abundant and what effects do they have on these organs?

-arterioles - contraction of vascular smooth muscle by alpha-1. Alpha-1 receptors are quite abundant in the peripheral vasculature -veins - increase in contraction by alpha-1 brings a lot of venous return to heart and thus increases preload. When you activate alpha-1, you increase preload and afterload because the heart needs to work harder. -liver - increased glycogenolysis by alpha-1 and thus increased blood glucose. -in male sex organ - alpha-1 stimulates ejaculation by vas deferens -bladder trigone/internal sphincter - alpha-1 causes urinary retention when tense

What part of the peripheral vasculature controls for the biggest change in peripheral resistance? What effect does activating alpha-1 receptors thus have on this part of the vasculature? What phenomenon does this explain when you're scared?

-arterioles are the other proportion of the peripheral vasculature that controls for the biggest change in peripheral resistance. -so activating alpha-1 increases total peripheral resistance and afterload (net effect - increased blood pressure) -why your extremities get cold when you're angry/scared

What happens in hypercalcemia?

-as [Ca2+] outside the cell increases, the amount of depolarization required to reach the action potential threshold is also increased. This means the threshold for action potential is increased. -In summary, it makes it more difficult to generate an action potential. -Symptoms (essentially opposite those of hypocalcemia) - fatigue, muscle weakness

What are the functions of the autonomic nervous system?

-assist the body to maintain a constant internal environment. e.g. provide motor control for viscera with effectors (smooth muscle, cardiac muscle, and glands); autonomic fibers in peripheral nerves are accompanied by visceral afferent fibers that originate from sensory receptors in the viscera - all work together to control the coordinated function. -accommodate coordinated responses to external stimuli (e.g. pupil response to ambient light; fight or flight response)

DM type I

-auto-immune - destruction of beta cells of pancreas -skeletal muscle and adipocyte cell membranes have insulin-sensitive glucose transporters. -In normal people, insulin receptor activation results in recruitment of transporters from a compartment within cytosol to the cell membrane. Increasing the number of GLUT transporters in a membrane increases the rate of glucose transport -People with DM I have insulin deficiency, so there are inadequate glucose transporters on the cell membrane. Have hyperglycemia because they can't use glucose quickly enough to prevent its build-up in their blood.

What kind of innervation does smooth muscle have?

-autonomic nervous system (NOT somatic motor)

What sympathetic receptors control the ciliary body epithelium? What effect do these receptors have on this structure when activated?

-beta-1 and beta-2 receptors control the ciliary body epithelium -These two receptors, when activated, will stimulate the production of aqueous humor.

What muscle do beta-2 receptors have an effect on? Review - what other receptor affects this muscle?

-beta-2 receptors (sympathetic) have some control of the ciliary muscle. Contribute minorly to mydriasis (pupillary dilation). -Mostly M3 receptors control the ciliary muscle (parasympathetic), leading to miosis (pupillary constriction)

What happens at the post-synaptic terminal?

-binding of transmitters to post-synaptic receptors -activation of receptors -elicitation of post-synaptic responses. These can be either excitatory or inhibitory (depends on function of receptor). Can then: -induce action potentials -activate post-synaptic signaling cascades

What are the major drugs to treat hypertension?

-calcium channel blockers -beta blockers (block adrenergic receptors) -ACE inhibitors and ARBs (target renin-angiotensin-aldosterone system) -vasodilators (cause relaxation of vascular smooth muscle)

How do alpha-2 *agonists* treat hypertension?

-centrally acting alpha-2 agonists activate alpha-2 receptors. Recall that alpha-2 receptors are the auto-receptors that take in norepinephrine from the cleft and lead to decreased synthesis/secretion of norepinephrine. The net effect of alpha-2 activation is less norepinephrine, which can thus treat hypertension.

Clathrin

-clathrin cage assembles on cytoplasmic side of membrane -clathrin attaches to membrane via adaptin. Adaptin is adhered to cytoplasmic tail domains of transmembrane proteins (specifically receptors in receptor mediated endocytosis). -membrane adhered to clathrin invaginates to form a clathrin coated pit -once clathrin cage is completed, the closed vesicle detaches from membrane -clathrin cage removed after vesicle detaches -highly specific and effective - used a lot in receptor mediated endocytosis

Calcium and membrane potential

-concentration of free Ca2+ in the cytoplasm is super low -most Ca2+ is sequestered in smooth ER -Eca is always a very large positive number (makes sense because there is a lot more Ca2+ outside than inside the cell) -membrane is impermeable to Ca2+ at rest, which means Ca2+ ions DO NOT CONTRIBUTE to resting membrane potential

What are the 2 main ways to modulate the excitatory state of smooth muscle?

-control calcium release to the cytoplasm -control activation state of myosin light chain kinase

What are the "CATS" of hypocalcemia?

-convulsions -arrhythmias -tetany -spasms and stridor

What G protein are M1 and M3 receptors coupled to and what effect are they related to?

-coupled with Gq protein -their activation leads to an increase in calcium concentration and activation of protein kinase C. Calcium concentration increases inside smooth muscle cells

Explain information flow within a neuron.

-dendrite collects electrical signals -cell body integrates incoming signals and generates outgoing signal to axon -axon hillock picks up electrical change. If threshold reached, it fires an action potential. Once an action potential is fired, it will travel down the axon uni-directionally until it reaches the terminal. Can then pass to other neurons' dendrites.

What are the smooth muscle cell's anchoring elements?

-dense bodies in cytoplasm -dense plaques in cell membrane

Where are beta-1 receptors abundant and what effects do they have on these organs?

-heart and kidney -heart/SA node - beta-1 activation increases heart rate (85% of the adrenergic receptors in the heart are beta-1 subtype). Beta-1 is associated with a stimulatory G protein. -heart/AV node - beta-1 activation increases conduction velocity -atrial and ventricular muscle - beta-1 activation increases the force of contraction, conduction velocity, cardiac output, and oxygen consumption in heart. If you activate beta-1, heart rate goes up and heart beats stronger. This causes increased oxygen consumption by heart. -His-Purkinje system - beta-1 activation increases the automaticity (ability of a particular tissue in heart to generate impulse) and conduction velocity. Normally SA node generates impulse, but the conductive Purkinje tissue also has ability to conduct the action potential. -Kidney - beta-1 activation increases renin release and eventually increases angiotensin-II and aldosterone. This also would contribute to increased blood pressure.

What are heterotropic interactions in cholinergic and adrenergic systems? Give examples. What is the significance of heterotropic interactions?

-heterotropic interactions - one neurotransmitter affects the release of another. -There are heteroreceptors for acetylcholine on the adrenergic (norepi, epi) nerve terminal. The nerve on the left in the figure secretes norepinephrine, but it has M2 receptors too! This means the secretion of adrenergic neurotransmitter (norepi, epi) is affected by the parasympathetic control.And vice versa - so on the nerve terminal for the cholinergic fiber (shown on right in the figure), there are alpha-2 receptors for norepinephrine. These heteroreceptors are subtype 2 (alpha-2 are present on parasympathetic fiber and M2 are present on sympathetic fiber). -This is how the parasympathetic/sympathetic systems work together to control each other and to coordinate tissue function.

What are homotropic interactions in cholinergic and adrenergic systems? Give examples.

-homotropic interactions - the idea that if you have an auto-receptor on the nerve terminal, then the neurotransmitter that is secreted from that terminal will come back and act on that auto-receptor to control (inhibit) the secretion of that same neurotransmitter. -e.g. norepinephrine (noradrenaline) coming back to the same nerve terminal from which it was released and binding to the alpha-2 subtype receptor. This will then decrease cAMP and inhibit calcium/inhibit secretion of norepinephrine. -e.g. acetylcholine binding to M2 receptor inhibits secretion/release of acetylcholine

Hyperpolarization and depolarization

-hyperpolarization - membrane potential becomes more negative -depolarization - membrane potential becomes more positive (less negative)

What are the characteristics of electrical synapses?

-if you inject current in cell A, it will flow through gap junctions to reach cell B. -bidirectional - if you inject current in cell B, it will go back to cell A. -small molecules (not just current) can go through gap junctions. This has low selectivity (if it fits, it goes through) -fast - you can stimulate enough in one cell to elicit an action potential in both cells. If you compare the time difference between the onset of the action potentials in the two cells, it is an extremely small time difference.

Explain myogenic response graphically. Explain transient phase.

-in figure - myogenic response - increased pressure in vessel (square wave). -Initially, that pressure causes distention of the vessel (diameter gets a little bigger) = transient phase. -Then, the muscle starts to contract = myogenic response. -In response to an increase in pressure, the vessel contracts. -Diameter gets smaller. -When you bring pressure back down, the vessel goes back to its previous diameter.

Why is there an increased voltage threshold for action potential generation in the relative refractory period?

-incomplete recovery of Na+ channels from inactivation (i.e. only some of the Na+ channels have left the inactivated state, so you need more stimulus to trigger the closed channels' voltage threshold??)

What is characteristic of multi-unit smooth muscle?

-individual muscle cells receive input from autonomic nerves and stimulate to contract on an individual basis -often found in airways or vasculature

Ion channels and their role in various potentials

-ion channels with no gates = maintain resting membrane potential. e.g. Na+ and K+ channels contribute to resting membrane potential. -voltage gated = contribute to action potentials -ligand gated = contribute to synaptic potential

What are the two major classes of post-synaptic receptors?

-ionotropic -metabotropic

What neurotransmitter do most of the postganglionic fibers of the sympathetic division of the ANS secrete? What are some other neurotransmitters? What are their receptors called?

-key neurotransmitter is norepinephrine. Their receptors are called adrenergic (like adrenaline). -some of the nerves (especially renal vascular smooth muscle) secrete dopamine as a neurotransmitter. Their receptors are called dopaminergic. -Adrenal medulla secretes epinephrine and norepinephrine, so it has adrenergic receptors.

If you see a lipid bilayer with ion channels (excitable membrane) as a circuit, what are its parts?

-lipid bilayer = capacitor -ion channel = resistor -current passing through this "circuit" produces voltage

What structures are found at a pre-synaptic terminal (bouton)? Describe the size of the synaptic cleft.

-lots of vesicles containing pre-synthesized neurotransmitters (ready to go!) -lots of mitochondria and ER (neurotransmission takes a lot of energy, so we need a lot of these organelles) -The synaptic cleft (space between pre- and post-synaptic terminal) is very narrow

Differential release of peptide neurotransmitters vs small-molecule neurotransmitters in low and high frequency stimulation.

-low-frequency stimulation - localized increase in Ca2+ concentration. Small-molecule neurotransmitters in small clear core vesicles are preferentially released. -high-frequency stimulation - more diffuse increase in Ca2+ concentration. Release of both type of neurotransmitter.

Give examples of primary chronic autonomic failure presentations. What do these examples function to demonstrate?

-many systems can be affected and each system may manifest in a different way -e.g. cardiovascular - orthostatic hypotension -e.g. sudomotor disorder - anhidrosis (heat intolerance) - clinicians don't really consider autonomic disorders -e.g. gastrointestinal - constipation, occasional diarrhea, dysphagia. Clinicians think about peptic ulcers, cancer, etc., but don't really consider an autonomic disorder as the cause of symptoms -e.g. renal and urinary bladder - nocturia (wake up at night to pee), etc. - clinicians consider referring to urology or nephrology and not the whole big picture. -e.g. reproductive - ED -e.g. respiratory - episodes of apnea (inspiratory gasps) -e.g. neurologic - Parkinsonian features -All of these examples function to demonstrate that there are so many different ways in which patients with autonomic function disorders can manifest. It's our job to think about the bigger picture.

What is the cell membrane and cytoplasm called in muscle cells?

-membrane = sarcolemma -cytoplasm = sarcoplasm

Say you have a cell with just sodium and potassium. The hypothetical cell membrane is only permeable to K+. Na+ extracellular is 142 and intracellular is 10. K+ extracellular is 4 and intracellular is 140. What happens?

-membrane potential is solely determined by K+ channels and K+ concentration gradient across membrane. K+ will leave the cell. -The Vrest = Ek = 61.5*log(4/140) = -95 mV. This means the cell will rest at -95 mV. This tells you the voltage difference that is high enough to antagonize the chemical driving force.

Say you have a cell with just sodium and potassium. The hypothetical cell membrane is only permeable to Na+. Na+ extracellular is 142 and intracellular is 10. K+ extracellular is 4 and intracellular is 140. What happens?

-membrane potential is solely determined by Na+ channels and Na+ concentration gradient across membrane. Na+ will enter the cell. -The Vrest = ENa = 61.5*log(142/10) = +70 mV. This means the cell will rest at +70 mV. This tells you the voltage difference that is high enough to antagonize the chemical driving force.

What is type II muscle fiber? What are its subtypes and their characteristics?

-more diverse - can produce relatively higher amounts of force, but this force production drops off relatively rapidly (especially in type IIb/x). Much faster than type I in terms of velocity of contraction. -two sub-types: -type IIa = fast oxidative; aerobic and anaerobic ATP; resistant to fatigue; moderate/rapid force output. -type IIb (type IIx) = fast glycolytic; anaerobic pathways for ATP; fatigue quickly; high/rapid force output. Note that type IIa fibers are like a hybrid between type I and type IIb fibers.

Ion channels

-movement of ions is determined by concentration gradient and membrane voltage difference -there are many types - no gate, voltage gated, ligand gated (extracellular neurotransmitter or intracellular second messenger), mechanically gated

Describe phasically active smooth muscle and give an example. Describe how membrane potential changes.

-muscles that are periodically active -e.g. intestines, within stomach where you're churning/mixing food -You have oscillations in membrane potential that bring membrane potential up to threshold and you get action potentials generated.

What are the major factors that influence action potential conduction rate/velocity?

-myelination -diameter/axon size (NOT length)

What is the intrinsic tone of smooth muscle called? What systems is it particularly important in?

-myogenic tone -This is particularly important in certain vascular beds that have to auto-regulate. -Auto-regulation - vascular beds can respond to changes in arterial pressure by changing the diameter of the vessel (constriction in elevated pressure and dilation in reduced pressure). This maintains relatively constant blood flow to the organ. (e.g. renal circulation and cerebral circulation).

What cells produce electrical signals when stimulated? (AKA are excitable cells)

-nerve cells -muscle cells Other cells have resting membrane potential, but don't produce electrical signals when stimulated.

Summarize post-synaptic events when an ion channel is involved.

-neurotransmitter binds to postsynaptic receptors -ion channels open or close -permeability and conductance change causes current flow -postsynaptic potential changes -postsynaptic cells are excited or inhibited -summation determines whether or not an action potential occurs

What are the 4 intrinsic activity patterns of smooth muscle? What is important to note about the activity of a tissue?

-normally contracted -tonically active -phasically active -normally relaxed -intrinsic activity patterns of smooth muscle reflect the specific function of the tissue it serves.

Explain the characteristics of nuclear bag fibers and nuclear chain fibers.

-nuclei within nuclear bag fibers are all congregating in the middle, hence the name "nuclear bag." They are responsive to static muscle length (so they'll fire at a given frequency and if you stretch the muscle, they'll fire at a higher frequency). Some of them are also responsive to dynamic changes in muscle length (so the rate at which you stretch a muscle will cause a relative increase in the number of action potentials from those fibers). -nuclei within the nuclear chain fibers are all arranged in a chain (hence the name "nuclear chain")

Voltage gated K+ channels

-one gate, two states -at rest = closed state -depolarization = open state

What features of the NMJ allow there to be strong synaptic transmission that ensures action potential generation?

-one motor neuron innervating a skeletal muscle fiber with multiple terminals from the neuron on that fiber -only excitatory input (no inhibition) -only acetylcholine and nAchR -multiple active zones at one terminal

Describe normally relaxed smooth muscle and give an example. What type of smooth muscle carries this out? Describe how membrane potential changes.

-only periodically contract -e.g. reservoir-like organs like the bladder need to stay relaxed to allow them to fill. They then contract when you're releasing urine. -Often carried out by single-unit smooth muscle and initiated by generation of action potentials. Action potential is the sole stimulus for generation of force. -Depolarize membrane to threshold and get firing of an action potential. You then get a certain amount of force generated depending on the frequency of the action potential firing (more frequent action potentials = more force)

What are some examples of neuropeptides (peptide neurotransmitters)?

-opioid peptides like substance P, vasopressin, oxytocin, and VIP-related peptides -endorphins -enkephalins -dynorphins

What traditional criteria define a compound as a neurotransmitter?

-packed into synaptic vesicles -Ca2+ dependent release -bind to specific receptors

Factors affecting rate of diffusion through channels

-permeability - # of open channels/% channels open -selectivity - physical structure of channel and distribution of charges in channel -concentration gradient (or electrochemical gradient in the case of ion channels)

Where are alpha-2 receptors abundant and what effects do they have on these organs?

-prejunctional nerve terminal - a negative feedback mechanism. Norepinephrine activates the prejunctional terminal alpha-2 receptor (auto-receptor). This causes a decrease in synthesis and secretion of norepinephrine. -platelets - activating alpha-2 causes platelet aggregation -pancreas - activating alpha-2 causes decreased insulin secretion

What systems do M3 receptors have a big effect on?

-quite abundant in bronchiolar smooth muscle - cause contraction/bronchospasm -M3 receptors are associated with a Gq protein. -If you activate M3 receptors, you will increase the concentration of calcium inside the smooth muscle cells. This causes contraction of bronchi/bronchioles -M3 receptors are also abundant in the bronchiolar submucosal glands, where they increase secretion and can narrow the lumen further. -M3 receptors are abundant in the stomach, which increases gut motility and causes cramps. -M3 receptors are also found in the intestine, where they cause contraction (with resulting diarrhea and stool incontinence). -M3 receptors in the bladder cause contraction of the detrusor muscle and peristaltic urethral contraction. M3 receptors inhibit (meaning they release) the external sphincter. -M3 receptors cause relaxation of most sphincters EXCEPT the lower esophageal sphincter -M3 receptors cause increased secretion of glands, including sweat glands (the weird sympathetic exception). All the other glands (besides sweat glands) are in parasympathetic situations. This includes salivation and lacrimation.

LDL (low-density lipoprotein) transport

-receptor mediated endocytosis of cholesterol via LDL receptors -hypercholesterolemia - some individuals lack LDL receptor. Results in high plasma levels of LDL cholesterol and can predispose them to CAD.

Active transport

-requires energy -requires a specialized carrier molecule -rate of transport approaches a maximum -shows chemical specificity and stereospecificity -can have competitive or noncompetitive inhibition -can be inhibited by metabolic inhibitors -can transport uncharged substances against a concentration gradient -can transport ions against an electrochemical potential gradient -primary active transport (pumps directly driven by ATPase) -secondary active transport (indirectly set up gradient by ATPase. Includes symport and antiport)

Vesicular transport

-requires energy and involves vesicles -endocytosis -exocytosis

What can myopathies result in?

-respiratory insufficiency/failure -increased susceptibility to respiratory infection -spinal curvature (scoliosis) -cardiomyopathy -metabolic abnormalities -reduced mobility/independence

Where is the basement membrane located in muscle? What is its function?

-sandwiched between cell membrane and endomysium -has basal and reticular laminas -A network of collagenous fibers, proteoglycans, glycoproteins, etc. -This is an anchoring point for proteins that come from within the cell that attach to the contractile elements of muscle and reach across the cell membrane and anchor in the basal lamina -Basal lamina serves as an anchoring point for the contractile proteins from within the cell -Need this anchoring point because they produce a force

What does each muscle spindle contain?

-several intrafusal fibers -two sensory afferent nerves -one efferent motor nerve (gamma motor neuron)

What are the different schemes for classifying smooth muscle?

-single unit -multi-unit

What is the dominant theory in how muscle contraction works?

-sliding filament theory - thick and thin filaments slide past each other -sarcomeres become smaller -Z line moves toward center of sarcomere -thick filaments pull thin filaments toward center of sarcomere -thin filaments pull the Z discs toward each other and the sarcomere shortens -Calcium enters intracellular space

What signaling cascades are major targets in the treatment of cardiovascular disease/hypertension?

-smooth muscle signaling cascades -act via G protein receptors to affect calcium release into the cytoplasm -or act via G protein receptors in calcium independent pathways, like relative activation state of myosin light chain kinase

What could increased fermented cheese consumption cause?

-some foods are rich in tyramine (fermented cheese). If you ingest a lot of these, you have the potential to increase norepinephrine (but we have a lot of mechanisms to degrade norepinephrine, so it's usually ok). -important in individuals using monoamine oxidase inhibitors (MAOI) because increased tyramine content could cause dangerously increased arterial blood pressure. That is because these individuals have these norepinephrine degradation mechanisms blocked.

How does the stretch reflex differ from the Golgi tendon reflex?

-stretch reflex = responds to muscle stretch -Golgi tendon reflex = responds to muscle tension

What are the main differences between type I and type II muscle fibers?

-velocity of contraction (type II is much faster at going through the cross-bridge cycle than type I) -ability to sustain force (type I can generate force for a long period time without fatiguing, whereas type I force production drops off rapidly) -different isozymes of myosin ATPase are why there are differences in speed between type I and type II muscle fibers. -type I (aerobic) fiber types have higher levels of myoglobin (myoglobin is an analog to hemoglobin, so it helps to buffer/hold on to oxygen in muscle. Myoglobin keeps a ready supply of oxygen in muscle. -As you would expect, muscles that primarily use oxygen to produce ATP have high levels of myoglobin. This causes qualitative differences in how muscles look (more myoglobin = muscle is redder in color). Type IIb fibers tend to be more pale due to lower amounts of myoglobin. -vascularization of muscle fibers (type I are highly oxidative fibers so they tend to have more blood supply. Type IIb fibers tend to have relatively less vascularization than type I). -Type IIa is a hybrid between type I and type IIb in terms of characteristics

What can smooth muscle dysfunction affect?

-vision -blood pressure -airway caliber -GI function -pregnancy/labor -reservoir/duct function (e.g. bladder)

Aquaporins

-water permeability of cell membrane is mediated by aquaporins (water channels) -osmosis rate increases with more aquaporins (water channels) in membrane -four aquaporin subunits make a channel -fast

What are the mechanisms by which denervation supersensitivity AKA withdrawal rebound hyperactivity (most common usage) AKA disuse hyperactivity works?

-when the stimulus is gone, the tissue is blocked. Those receptors are not stimulated anymore. The tissue senses the lack of stimulus and builds more receptors to make up for it. So when stimulus returns (you take away the block), you have a ton of receptors ready to respond and if you have the same concentration of neurotransmitter, the response will be super strong. -another cause - loss of mechanisms for removal of neurotransmitter

What does the ciliary body epithelium produce? Describe the path of this substance produced.

-where aqueous humor is produced -aqueous humor then goes through the pupil to the anterior chamber, then anterior to the lens, into the angle between the cornea and the iris, through the trabeculae meshwork, and exits through the canal of Schlemm

Explain the latch state in detail.

-where you can stop the cross bridge cycle in the middle. Happens when cytoplasmic calcium starts to fall and therefore phosphorylation of the myosin light chain is decreased. -Myosin head is phosphorylated, cocked, and then makes contact with the actin filament and goes through the power stroke (still attached). -Myosin light chain phosphatase then comes in and pops the phosphate group off. -This causes the myosin head to freeze and you're in the latch state. You're still maintaining tension, but the cross bridge cycle does not proceed. The affinity of myosin head for ATP goes way down. -If you're not going through the cross bridge cycle, you're not using ATP. BUT, you're still maintaining muscle tension. -If myosin light chain kinase comes in again (while the latch state is going on) and re-phosphorylates the myosin head, then you can proceed with the cross bridge cycle.

How do local anesthetics work?

-work in two ways -can penetrate through the membrane to block Na+ channels from the inside -can also stay inside the bilayer and block Na+ channels within the bilayer -inhibit action potential generation to reduce pain sensation

Label 1- 7 on the figure

1 - Z disc 2 - actin/thin filament 3 - myosin/thick filament 4 - I band 5 - A band 6 - M line 7 - H zone Need to know 6 and 7!

How is excess acetylcholine removed from the synaptic cleft?

Acetylcholinesterase

What happens to leftover acetylcholine in the synaptic cleft? Why is this important?

Acetylcholinesterase degrades acetylcholine in the synaptic cleft - ensures neurotransmission isn't continuous

Outline differences between action potentials and synaptic response (local potentials)

Action potential: -threshold for generation -all or none -voltage gated Na+ channels -active conduction -spread in a non-decremental fashion Synaptic response (local potential): -mediated by ligand-gated ion channels -transient Vm shift in a localized area. Shift may be in depolarizing or hyperpolarizing direction. -graded potential - amplitude is proportional to size of stimulus -decremental spread

Chemical driving forcce

An ion's own chemical concentration gradient exerts a chemical driving force on the ion, which makes it move from high to low concentration.

A 51-year-old female experienced frequent "attacks" when her heart raced and pounded; she had a throbbing headache and visual disturbances; she felt hot, but her hands and feet were cold. The family doctor thought these were menopausal symptoms and prescribed hormone replacement therapy over the phone. The medication did not relieve the symptoms. -Office visit & labs: -Vitals: BP 200/110, HR 120 bpm, 24-hr urinary 3-methoxy-4-hydroxymandelic acid (VMA) positive -CT scan: 3-cm mass on the right adrenal gland -Dx: pheochromocytoma (a tumor that secretes a lot of catecholamines in the body) Why don't we see reflex bradycardia?

Because the nerve systems are overwhelmed with catecholamines. The reflex mechanisms are overridden/overwhelmed because the tumor keeps secreting catecholamines.

How do nicotinic acetylcholine receptors (nAchR) work?

Binding of Ach (the ligand) to this receptor opens its channel and allows Na+ influx and K+ efflux (Na+ permeability is MUCH greater than K+ permeability). Net effect = current influx.

What is the calcium sensor in smooth muscle?

Calmodulin

What is the main mechanism of adrenergic receptors?

G protein coupled receptors

What are intrafusal fibers made up of?

Combo of 2 nuclear bag fibers (1 static and 1 dynamic) and 5 nuclear chain fibers attached along the length of the nuclear bag fibers

Na+/K+/Cl- co-transporters

Cotransport of 1 Na+ : 1 K+ : 2 Cl- from extracellular fluid to cytosol. Can be found in kidney (inhibited by diuretics - to treat HTN)

Which of the following synaptic transmissions has the shortest synaptic delay (inhibitory synapse, NMJ, CNS synapse with ionotropic receptors, electrical synapse, or CNS synapse with metabotropic receptors)?

Electrical synapse - gap junction makes things supa fast

What would happen if a mutation caused a slower rate of inactivation of voltage gated Na+ channels?

If a mutation causes a slower rate of inactivation of voltage gated Na+ channels, the action potential becomes wider

What is histamine's receptor?

H receptors (1-4 subtypes). Histamine is a diamine.

Where are beta-1 adrenergic receptors abundant?

Heart and kidney (stimulates renin secretion)

What drugs can inhibit acetylcholine synthesis?

Hemicholiniums can block the choline transporter, thus inhibiting the synthesis of acetylcholine. These are not used in practice, but they are instead used to study the drugs that we actually use.

The enzymatic activity of the myosin head allows it to perform which of the following functions? (synthesize ATP, hydrolyze ATP, bind calcium, or expose the active site on the actin filament)

Hydrolyze ATP

What happens if you treat a hypokalemic patient with K+ too fast/too much?

Hyperkalemia - Depolarization of membrane potential

What interconnects dense bodies/plaques?

Intermediate filaments. Contractile elements in smooth muscle are linked to each other via intermediate filaments.

Types of electrical signal

Local = -receptor potential (like photo response, e.g.) -synaptic potential (synaptic potentials are the incoming signals to the neuron and are considerably smaller than an action potential. When the neuron is depolarized to threshold, it generates an action potential. The action potential is the outgoing signal of the neuron.) Active = action potential

What type of muscarinic receptor is very common in the eye? What muscles does this receptor relate to?

M3 receptor - relates to control of the pupillary sphincter and the ciliary muscle.

Sodium co-transport

Sodium ions move down their concentration gradient. This energy loss drives movement of another molecule against its concentration gradient (in the same direction as sodium). Glucose in glucose reabsorption of the kidney (two sodium to one glucose), e.g.

What drug inhibits catecholamine synthesis?

Metyrosine blocks tyrosine hydroxylase

What 3 ions contribute to the in vivo membrane potential? Which is the most important?

Sodium, potassium, and chloride. Potassium is the most important of these three.

What's the net effect of cholinergic activation in the eye?

Miosis and near accommodation (due to activation of M3 at pupillary sphincter muscle and ciliary muscle).

What disease is caused by an antibody against the nicotinic receptor?

Myasthenia gravis

What response is inherent to smooth muscle, underlies auto-regulation of vasculature, and is independent of neural, metabolic, and hormonal influences?

Myogenic response

Na+/Ca2+ exchanger

Na+ moves into the cell (down its gradient) and pumps Ca2+ out of the cell (against its gradient).

What causes the undershoot/hyperpolarization phase of an action potential?

Prolonged opening of voltage-gated K+ channels

What do electrical synapses consist of?

One or more *gap junction channels* permeable to ions and small molecules. Electrical synapses bring the two sides of the membranes (cell 1 and cell 2) closer together.

Active vs passive conduction

Passive conduction - has decay with distance Active conduction - no decay with distance (how you can get motor neurons to signal from spinal cord to toes)

How is the glucose concentration gradient maintained?

Phosphorylation of glucose once it's inside the cell membrane (to make G-6-P). G-6-P can't leave the cell, so this keeps the glucose concentration gradient high by allowing more glucose to come in the cell.

What is adenosine's receptor? What does it do?

Purinergic receptor. CNS depressant.

What contributes to motor control by integrating proprioceptive information with motor programs to produce finely tuned movements?

Sensory features of muscle that also contribute to control of motor programs

Exocytosis

Stuff inside the cell is packaged into vesicles and excreted into extracellular medium (e.g. release of neurotransmitter at synapse and release of hormones from endocrine cells)

Time constant of excitable membranes

The amount of time it takes for the voltage to change by 63% of the eventual steady value. Expressed in the equation tau = resistance*capacitance -Time to charge a capacitor makes a wave shaped curve -A bigger time constant means it takes longer for the membrane to charge, as determined by resistance and capacitance

What are the directions for the chemical and electrical forces on K+ when a neuron is at its resting membrane potential of -65 mV? Which force is stronger (assume Ek is -90 mV)? K+ extracellular is 4 and intracellular is 140.

The electrical force pushes K+ in and the chemical force pushes K+ out. The chemical force is stronger. We know this because we still have a high concentration of K+ inside the cell and a low concentration of K+ outside the cell. This tells you that chemical driving force is pushing K+ out. Since K+ is leaving (and K+ ions are positive), the inside of the cell becomes negative. The electrical driving force will try to push K+ back in to balance charge. The chemical force is stronger. Graphically (see PPT slide #17), the electrical driving force is measured between 0 mV and the resting membrane potential at -65. The chemical driving force is measured as the equilibrium potential of K+ (which is between 0 mV and -95). Recall that Ek is measured in mV, but really represents the concentration gradient.

Explain the relationship between axon diameter and action potential conduction velocity.

The larger the axon diameter, the faster the axon conducts action potentials. -conduction velocity is proportional to the square root of axon radius (e.g. radius of 4 has speed of 2. To double the speed, you'll have to quadruple the radius).

Define autonomic nervous system. What are the key words of the definition?

The portion of the nervous system that controls the most visceral functions and accommodates coordinated responses to external stimuli. Key words - visceral (can't control) and coordinated (bring up one system and bring down another system so the response to the external stimulus is most optimal).

What are the different muscle sensory afferent nerves?

There are group 1a and group 2 afferents - these take info from muscle spindles back to the CNS

If sympathetics cause beta-2 receptors in the liver to increase glycogenolysis to raise blood glucose, why does beta-2 also stimulate the pancreas to increase insulin secretion?

This seems contradictory with the liver in this system (because it's increasing blood sugar) -BUT you do glycogenolysis to increase blood sugar for muscles to use it. You increase insulin to bring that sugar into your muscle.

Two major categories of membrane transport

Vesicular and non-vesicular (passive and active transport)

What is the Goldman-Hodgkin-Katz equation? What is important to note about p?

Vm = RT/F * ln ((pk[K+]out + pna[Na+]out + pcl[Cl-]in)/(pk[K+]in + pna[Na+]in + pcl[Cl-]out)) p = permeability coefficient for a given ion The greater an ion's permeability, the greater "presence" it holds in the equation. And, therefore, Vm is closer to the equilibrium potential of that ion. At rest, the cell's membrane potential balances between Ek and Ena. The cell is much more permeable to Ek, so the membrane potential is closer to Ek.

Which of the following is a property of action potentials, but not local potentials (graded potential, voltage gated Na+ channels are involved, size of potential depends on strength of the triggering stimulus, can be a hyperpolarizing potential, spread in decremental fashion)?

Voltage gated Na+ channels are involved in action potentials, but not synaptic responses

Describe the effect of motor unit activation on muscle fibers.

When you activate a motor unit, the muscle fibers that it activates are typically spread diffusely throughout the muscle (because you want to have an even muscle contraction and an even distribution of force)

Give an example of the Golgi tendon reflex.

You have a muscle being activated and generating tension - Golgi tendon organ is activated and sends info back to the spinal cord, where it synapses with an inhibitory interneuron. This partially inhibits the alpha motor neuron (keeps it from being overactivated).

What happens when depolarization stimulus is weak?

You only get a passive response

What does tendon/aponeurosis do?

anchor muscle to bone

Carrier proteins

mediated transport that requires two or more substances be moved through the membrane -symport - substances move in same direction (co-transport) -antiport - substances move in opposite directions (exchange transport or countertransport)