MERP Physiology Mini 1

Na channel regulation

-At rest one gate is closed (activation) and one is open (inactivation) -Activation gate: opens rapidly with depolarization -Inactivation gate: closes slowly with depolarization During repolarization: membrane must repolarize to reset gates

What are the four ways chemical signals interact with cells?

1. Ion channel 2. Enzyme-linked 3. G-protein coupled (GPCR) 4. Intracelular (nuclear)

Antiporter

Carrier protein can move molecules in opposite direction.

K channel regulation

Have one gate; open slowly in response to membrane depolarization; K efflux causes the membrane potential to become more negative.

Contrast voltage-gated Na and K channels and describe their states during the phases of an action potential

Threshold: the membrane potential at which Na-channels open; Rising phase: period during which Na channels are open; Overshoot: magnitude depends upon how long Na channels remain open; Peak: defined by the closing of Na-channel and opening of K channels; Repolarization: opening of K-channels; Hyperpolarization: continued opening of K-channels

Six modes of cell to cell communication

Touching: gap junctions; intercellular adhesion molecules Messages via receptors on cell membrane: autocrine; paracrine; nerves; endocrine; neuroendocrine

Force-velocity relationship

-As load increases shortening velocity decreases -At maximum load shortening velocity is zero=isometric contraction -At zero load shortening velocity is maximum -Maximum shortening velocity is a function of myosin ATPase activity

Contrast the length-tension and force-velocity relationships; describe mechanisms of each; be able to diagram each

-At zero load=velocity is maximum; related to myosin ATPase activity in muscle -red (slow) muscle: lower maximum shortening velocity than white muscle because myosins have different ATPase activities -Velocity changes with size of afterload; myosin cycling rate influenced by load on each cross-bridge> as load increases, load on each x-bridge increases> slowing rate of cycling -Contractions begin as isometric and transition to isotonic if the load is lifted; if the load is not lifted, contraction remains isometric -Preload vs. afterload: a) passive tension (or force) produced by stretching muscle is called preload; applied prior to contraction b) active tension needed to lift a load is called afterload; force contractile proteins generate after stimulation -Heart: a) volume of the ventricle prior to contraction is preload; aortic pressure is an example of afterload b) increasing preload toward maximum preload, increases force without changing maximum velocity c) P = work / time; P = F x V; how fast work is done

Differentiate between isometric and isotonic contractions; between a twitch and a tetanic contraction

-Isometric contraction: contraction without shortening; shortening velocity is zero; maximum load reached -Isometric contraction: contraction with shortening velocity -Twitch: single mechanical response initiated by a single action potential -Tetanus: short duration of skeletal muscle action potential relative to mechanical response; intracellular Ca can be kept elevated by increasing action potential frequency> increase in stimulation frequency results in summation of contractile response> fusion of twitches into a sustained constant level of force

Describe effect of changes in preload on the force-velocity relationship

-Maximum shortening velocity depends on myosin activity; high maximum velocity of shortening=high myosin ATPase activity -Changing preload: a) will change both isotonic and isometric force b) will alter shape of force-velocity curve i) maximum (isometric) force will change ii) maximum shortening velocity will not change c) as preload increases, shortening velocity will increase -Heart: changes in preload influence a) strength of pumping b) speed of shortening

Define preload and afterload; give an example of each

-Preload and afterload: a) passive tension (or force) produced by stretching muscle is called preload; applied prior to contraction b) muscle develops active tension in order to lift an afterload; force contractile proteins generate after stimulation; weight muscle is trying to lift; greater the weight, greater the afterload -Heart: a) volume of the ventricle prior to contraction is preload; aortic pressure is an example of afterload b) increasing preload toward maximum preload, increases force without changing maximum velocity -Power=work / time; P = F x V; how fast work is done

Contrast the organization of contractile filaments in smooth muscle and striated muscle

-Responsible for contractility of hollow organs: blood vessels, GI tract, bladder, uterus -can develop isometric force per cross-sectional area that is equal to that of skeletal muscle but slower speed of contraction than skeletal muscle -Organization a) less ordered contractile filaments b) no troponin in thin filaments c) dense bodies serve the function of Z-bands d) myosin thick filaments "side-polarized" not "end-to-end" as in striated muscle e) connected together by tight-junctions; not tendons or bones for attachment -Autonomic nervous system control a) regulation controlled by diverse function of smooth muscle containing organs: i) GI: triple innervation plus automaticity ii) Uterus: innervation plus hormones iii) VSM: sympathetic nerves plus hormones (epinephrine, angiotensin II) and paracrine factors (NO) b) receptor distribution

Describe the location and function of the following structural components of muscle: sarcomere, sarcoplasmic reticulum, T-tubles, triad, thick filaments, thin filaments, Z-band, A-band, I-band

-Sarcomere: contractile unit of striated muscle; The area between two Z-bands -Muscle fiber: individual muscle cell; multinucleated -Sarcolemma: muscle cell membrane -Myofibrils: composed of myofilaments> thick (ATPase myosin containing) filaments and thin (actin/tropomyosin/troponin containing) filaments -Sarcoplasmic reticulum: myofibril is surrounded by a smooth endoplasmic reticulum called the sarcoplasmic reticulum (SR); storage site for calcium -T-tubles: sacrolemma invaginates between myofibrils -Triad: where T-tubules come close to ends of sarcoplasmic reticulum -A-bands (thick and thin filaments) -I-bands (thin filaments only) -H-band (thick only) -Z-band (or line): where the ends of thin filaments connect

Differentiate between a motor pool and a motor unit

-Upper motor neurons have cell bodies in motor cortex in brain; innervate lower motor neurons in spinal cord -Lower motor neurons have cell bodies in anterior horns of the spinal cord and send axons through ventral horn to skeletal muscle cells -Sensor neurons send information from the muscle cells to the CNS -Motor unit: collection of muscle cells innervated by same motor nerve and its branches -Motor pool: collection of motor nerves innervating all cells within a whole muscle

Contrast the length-tension and force-velocity relationships in smooth and striated muscles

-length-tension relationship indicating sliding-filament hypothesis is true even though organization of thick/thin filaments is not highly ordered as striated muscle -can develop higher level of force over wider range of stretched lengths a) due to filament organization within cell b) myosin thick filament has side-polarized organization -exhibits a force velocity relationship: a) maximum shortening velocity is less than striated b) maximum force (isometric) is comparable

Describe the relationship between membrane potential changes and contractile response

-smooth muscle contraction and changes in membrane potential not tightly linked together; lots of variation -contraction may or may not require an action potential -shape of smooth muscle action potentials also varies 1. resting membrane potential is less negative (~40 mV inside negative) than striated muscle or nerves 2. duration of action potentials also varies

Explain how hyper/hypokalemia and voltage-gated Na channel blockers alter the action potential

1. Hyperkalemia: increase in extracellular [K] -causes depolarization -brings closer to threshold -sustained depolarization closes Na inactivation gates -more likely to fire an action potential 2. Hypokalemia: low extracellular [K] causes action potential to not fire as easily -threshold is more negative farther to go to get back to resting phase 3. Digitoxin/ouabain: blocks N-K ATPase; resting membrane potential is effected 4. Ciguratoxin: binds to Na-voltage gated channels and keeps them in active/open state 5. Tetrodotoxin: binds to Na-voltage gated channels and keeps them in the inactive/closed state Symptoms: -Na-K ATPas inhibition: slow membrane depolarization towards zero, but not much -Opening of Na channels: membrane potential approaches Na equilibrium potential; makes cell more positive -Closing/blocking Na channels: no action potential can be generated

Characterize the properties of diffusion

1. Lipid soluble molecules can cross membrane via simple diffusion down (with) its concentration gradient. 2. Pores or channels help small, uncharged diffusion 3. No ATP used. 4. Rate is determined by: a) Molecule size: small faster than large b) Transmembrane concentration gradient: bigger the gradient, the faster c) Membrane thickness: thinner faster than thicker d) Membrane surface area: the larger the faster

Name the transmitters and receptors at pre/postsynaptic synapses in both branches of the autonomic nervous system and the somatic nervous system

1. Receptors: transmembrane proteins a) nicotinic receptors: ion channels b) adrenergic & muscarinic: coupled to intracellular second messengers 2. Sympathetic: a) Pre: Ach> nicotinic (N2 or NN) b) Post: NE> alpha, beta 1, beta 2 3. Parasympathetic: a) Pre: Ach> nicotinic (N2) b) Post: Ach> muscarinic (M-M5) 4. Somatic motor axons: a) Ach> nicotinic (N1 or NM) 5. Adrenal: a) Pre: Ach> nicotinic (N2)> E & NE into blood

Regulation of Contractile Protein Interaction

1. Thick filament regulation vs. thin filament regulation a) most common process for regulating molecular motors b) thin filament does NOT contain troponin c) cytoplasm contains calmodulin d) Ca initiates cascade of events leading to phosphorylation of myosin> enables myosin to bind actin 2. Inactivation: free intracellular Ca concentration reduction and removal of phosphate from myosin 3. cAMP activates a kinase that inactivates MLCK by phosphorylation 4. other intracellular mediators may increase the activity of MLCP (e.g. cGMP)

Define osmosis and characterize the properties of a molecule that causes osmosis.

1. Water moves by diffusion down its concentration gradient. 2. Osmolarity is the concentration of particles in solution. More particles, less water and expressed as Osm/L. Blood=290 mOsm/L (all molecules dissolved in blood) 3. Water is drawn towards solutions with higher osmolarity (lower water) 4. The number of membrane impermeable molecules drives osmosis 5. Osmotic pressure is driving force. It "sucks." 6. Osmolality=Osm/kg of liquid

Define terms that describe an action potential: threshold potential; overshoot; hyperpolarization; refractory period

Action potential: sudden change of resting membrane potential in which potential moves toward zero and even reverses, becoming positive on the inside of the cell. The action potential results from the rapid opening and closing of specific ion channels. Threshold: potential that activates (opens) voltage-gated ion channels; positive ions to enter/or negative ions to leave Overshoot: potential goes beyond zero and the inside of the membrane becomes positive relative to the outside Repolarization: initiates return of membrane potential to its resting value Hyperpolarization: membrane potential moves beyond resting (more negative) value before once again returning to the resting value Absolute refractory period: closure of the inactivation gate of the Na-channel; no action potential is possible during this period Relative refractory period: open K channels which moves the membrane potential farther from threshold potential requiring a greater depolarization to open Na-channels

Predict the net driving force for Na, K, Cl, Ca ions given the membrane and equilibrium potentials

Basic conditions: 1. Na-K ATPase generates a transmembrane concentration gradient for Na and K; K high inside, Na high outside 2. Membrane leaks K and is essentially impermeable to Na & Ca 3. Cell cytoplasm contains impermeant anions 4. The inside of the cell is negative relative to the outside, this transmembrane electrical gradient is called the resting membrane potential The resting membrane potential is usually between -70 and -90 mV. This means that the equilibrium potentials for K and Cl are close to the resting membrane potential. While the equilibrium potentials for Na and Ca are far from the resting membrane potential. This means there is a large electrical driving force for Na & Ca influx which can be tapped by opening their channels

Describe ways in which neuormuscular transmission can be altered

Botulinus toxin ("Botox"): produced by Clostridium botulinum; prevents release of ACh from motor nerves; antitoxin and respiratory support Curare: plant poison (Strychnos toxifera) if gets into blood; binds to nicotinic receptor on motor end plate> blocks binding of ACh; does not bind synaptic (N2) nicotinic receptors; competitive inhibitor; asphyxiation; blocking acetylcholine esterase Neostigmine: synthetic compound blocking active site on acetylcholinesterase inhibiting its action enhancing effect of ACh; peripheral nervous system (heart, skeletal muscle, GI-tract); improve skeletal muscle function in myasthenia gravis Hemicholinium: synthetic compound; blocks choline reuptake into neuromuscular junction; experimental purposes

Outline the sequence of events resulting in force generation

Ca binding to Tm-Tn complex opens myosin binding sites on actin> myosin-ADP Pi complex binds to actin> conformational changes in myosin generate force and release ADP + Pi> power stroke occurs with Pi release> ATP binding to myosin resets myosin> cycle repeats as long as Ca is present

Counter-transport

Carrier protein can move molecules in opposite direction.

Cotransport

Carrier protein can move molecules in the same direction.

Symporter

Carrier protein can move molecules in the same direction.

Characterize the properties of secondary active transport

Carrier protein uses energy from the down-hill movement of one molecule to move a second molecule. Can move molecule against (up) its concentration gradient. No ATP used.

Characterize the properties of facilitated diffusion

Carrier-mediated movement of molecules through membrane. Binds to molecule on one side and releases it on the other. Moves molecule down (with) its concentration gradient. No ATP used.

Describe the significance of nerve diameter, length constant and time constant on conduction; describe the effect of multiple sclerosis

Diameter: conduction velocity increases with diameter; internal resistance decreases when the diameter increases Length constant: distance current spreads; longer is better; larger the membrane resistance (Rm) the less likely charge will escape from the cell; the smaller the internal resistance (Ri) the easier it is for current to flow along the length of the nerve or within the cell. Time constant: time it takes to change membrane voltage at stimulation point; shorter the time constant the better Multiple sclerosis: degeneration of CNS myelin; reduced action potential conduction rate and alterations in CNS function manifested as sensory abnormalities and motor problems.

Differentiate between events producing an EPSP and an IPSP

EPSP: Presynaptic neurotransmitter opens ligand-gated Na channels causing Na-ion influx and depolarization of postynaptic membrane; membrane potential closer to threshold; excite IPSP: Presynaptic neurotransmitter (GABA); opens ligand-gated Cl channels causing Cl- ion influx and hyperpolarization of postsynaptic membrane; membrane potential is further from threshold; more negative; harder to excite

Describe how synaptic communication can summate

EPSPs or IPSPs can be increased through: Spatial summation: summing of effects at different places on the same neuron Temporal summation: summing of effects that occur at the same time on the same neuron

Effects of parasympathetic stimulation

Heart: M2> decrease HR Vasculature: minimal effect Bronchioles: M3> constriction Eye: M3> constricts pupil (circular muscle contraction) GI tract: M3> smooth muscle contraction/sphincter relaxation/increased salivary, gastric, pancreatic secretions Male genitalia: M3> erection (point) Sweat: no effect Bladder: M3> smooth muscle contraction/internal sphincter relaxation

Characterize the properties of active transport

Identical to facilitated diffusion but carrier protein uses ATP to move molecule. Moves molecule against (up) its concentration gradient.

Describe the process of EC-coupling in smooth muscle

Intracellular Ca++ concentrations increase when Ca++ enters cell and is released from sarcoplasmic reticulum> Ca++ binds to calmodulin> Ca++-calmodulin activates myosin light chain kinase (MLCK)> light chains are phosphorylated in myosin heads> increases myosin ATPase activity> active myosin crossbridges slide along actin and create muscle tension> free Ca++ in cytosol decreases when Ca++ is pumped out of cell or bak into sarcoplasmic reticulum> Ca++ unbinds form calmodulin> myosin phosphatase removes phospate from myosin, which decreases myosin ATPase activity> less myosin ATPase results in decreased muscle tension

Contrast the three types of membrane channels

Ion channels behave as though they had gates that open and close under specific conditions. When the gate is closed, no ions can pass through the channel. The opening of ion channels is controlled in a several ways. Some channels are sensitive to: Stretch-activated Ligand-gated (e.g. hormones, transmitters, ions, drugs) Voltage-gated

Describe the events from a motor nerve action potential to muscle contraction and the role of miniature end-plate potentials

Lower motor neuron releases ACh> ligand-gated Na-K channels (nicotinic receptors) on motor end plate open> end plate potential (EPP) is generated> EPP depolarizes adjacent muscle cell membrane to threshold> each ACh vesicle depolarizes motor end plate potentials (MEPP)> sufficient ACh release to depolarize motor end plate to 0mV> muscle action potential produced

Define equilibrium potential and list three factors that determined its value for an ion

Membrane potential at which the electrical and concentration gradients for an ion are equal and opposite is called, equilibrium potential. The magnitude of the equilibrium potential depends upon: 1) permeability of the ion; 2) concentration gradient; and 3) the valence of the ion If the permeability is zero, there will not be an equilibrium potential for that ion. The larger the concentration gradient, the larger the equilibrium potential The smaller the valence, the larger the equilibrium potential

Describe the ionic basis of action potential propagation in myelinated vs. unmyelinated axons

Myelin increases conduction speed Saltatory conduction: restricts transmembrane ion flow to inter-nodal areas where there is a high density of voltage-sensitive Na-channels

Describe the cause of the two refractory periods of an action potential

Refractory periods 1. Absolute refractory period is due to closure of the inactivation gate of the Na-channel; no action potential is possible during this period 2. Relative refractory period is due to open K channels which moves the membrane potential farther from the threshold potential requiring a greater depolarization to open Na-channels

Distinguish between diffusion, facilitated diffusion, active transport and secondary active transport from experimental data.

Simple diffusion: rate of flux is a linear function of solute concentration. The greater the concentration gradient, the faster the rate of movement. Carrier-mediated transport: there is a maximum rate of flux

Contrast the process of excitation-contraction coupling in skeletal and cardiac muscles

Skeletal muscle: action potential in sarcolemma> travels down T-tubule> voltage-sensitive ion channels: dihydropyridine receptors (DHP-receptors)> transmembrane proteins make physical contact with Ca-channels in SR-membrane called: ryanodine receptors (RyR-receptors)> mechanically coupled> four DHP-receptors associated with each RyR-receptor> DHP receptor conformational change> conformational change in RyR-receptor> RyR receptor opens allowing Ca to diffuse out of SR through into cytoplasm> rapid excitation-contraction coupling> stop contracting and relax when intracellular Ca concentration is returned to a low value> Ca taken back into the SR by Ca-ATPase pump (primary active transport) located SR membrane> Cardiac muscle: action potential> DHP-receptors act like voltage-gated Ca-channels (also called L-type Ca-channels)> open in response to depolarization> small amount of Ca> cytoplasm> Ca binds to RyR-receptors on SR membranes> open> Ca leaves the SR through open RyR-receptors> . Ca-induced-Ca-release> slower excitation-contraction coupling> extracellular Ca is needed to release SR Ca> Ca removed from cytoplasm in three ways: 1.Taken up into SR by Ca-ATPase pump; 2.Exchanged with extracellular Na via carrier mediated Na-Ca countertransporter; 3. Pumped out of cell by a membrane Ca-ATPase pump

Hypotonic solution

Solution has few impermeable molecules than blood. Cell swells because water will move into cell due to higher cellular osmolarity than the surrounding solution.

Hypertonic solution

Solution has more impermeable molecules than blood. Cell shrinks because water leaves the cell due to higher osmolarity in surrounding solution.

Isosmotic solution

Solution has same number of particles/volume as blood

Isotonic solution

Solution has the same number of impermeable particles/volume as blood. Need to know if particles can cross cell membrane in order to differentiate between isosmotic and isotonic.

Length-tension relationship

Stretching a muscle changes tension on connective material and changes thin-thick filament overlap Passive tension=connective tissue tension Active tension=contractile protein tension optimal length=best thick-thin filament overlap

Describe the roles of the autonomic and somatic nervous systems in the micturition reflex

Sympathetic -Active during filling -relax detrusor muscle -Contract internal sphincter Parasympathetic -activate during emptying -contract detrusor muscle -relax internal sphincter Somatic -contract external sphincter -requires higher centers & is learned

Contrast the responses of the following structures to sympathetic and parasympathetic nerve stimulation: heart, vasculature, bronchioles, GI tract, sweat glands, bladder, eyes

Sympathetic stimulation: Heart: B1> increase HR/force Vasculature: a1> contraction Bronchioles: B2> relaxation Eye: a1> pupil dilation (radial muscle contracts) GI tract: B2> smooth muscle relaxation/decrease motility a1> sphincters contract B1> increase salivary secretion Male genitalia: a1> ejaculation (shoot) Sweat: M3> increase sweating Bladder: B2> smooth muscle relaxation a1> internal sphincter contracts Kidney: a1> vasculature> constriction B2> renin release

Sequence the ionic and molecular events that mediate chemical synaptic communication; describe at least three ways in which synaptic transmission can be altered

Synapse - nerve to nerve connection; proximal nerve is presynaptic, distal nerve is postsynaptic Ganglia - collection of synapses Neuromuscular junction - nerve to skeletal muscle Synaptic transmission Axonal AP> voltage-gated Ca-channels to open> vesicle fusion and release of transmitter> opening of ligand-gated ion channels on postsynaptic dendrites> change in postsynaptic nerve cell membrane potential Altering synaptic transmission: 1. Transmitter release: presynaptic nerve fcn (TTX), Ca-channels, extracellular Ca 2. Transmitter action: receptor antagonists; curare 3. Transmitter degradation: acetylcholine: acetylcholinesterase; norepinephrine: monoamine oxidase (MAO), catechol-O-methyl transferase (COMT) 4. Transmitter disposal: reuptake- cocaine

Describe the Nernst equation and what it predicts

The Nernst equation predicts the equilibrium potential based on ion concentrations and ion valence; it assumes the molecule can diffuse across the cell membrane.

Describe the generation and maintenance of the resting membrane potential with particular reference to the roles of K ions and the Na-K ATPase

The primary cation inside the cell is potassium which can cross the membrane through K-channels. The major anions are proteins, phosphates and sulfates all of which cannot cross the cell membrane. Because there is a concentration gradient favoring K diffusion out of the cell, it moves down its concentration gradient leaving behind impermeable anions. This separation of charge makes the inside of the cell membrane slightly negative relative to the outside of the cell membrane. This electrical potential difference is called the resting membrane potential and is present in all cells of the body. The number of K ions that move to generate the resting membrane potential is very small (~ 6x10-13 moles/cm2). Because of this there is not a measurable change in either the intracellular or extracellular K concentrations. This also means it would take a long time for the K concentration gradient to dissipate and cause the resting membrane potential to go to zero. To sustain (maintain) the high intracellular K concentration, the Na-K ATPase pump moves two K ions into the cell in exchange for three Na ions out of the cell. Because more positive ions leave than enter the cell during this exchange, the pump is said to be "electrogenic". It makes the cell slightly more negative inside. Do not confuse the role of K diffusion and the role of the Na-K ATPase pump in generating the resting membrane potential. The membrane potential is due to the diffusion of K from the cell. The pump just keeps intracellular K concentration high. Inhibiting the Na-K pump will only produce a small change (depolarization) in membrane potential. It will not prevent the membrane potential. The membrane potential will continue until the K concentrations are the same on both sides of the cell membrane.

Contrast the characteristics of Type I and Type II muscles

Type I fibers vs. Type II fibers 1. Type I -Red fibers -Slow twitch (slow oxidative/fatigue resistant fibers) -Contain: a) Large amounts of myoglobin. b) Many mitochondria. c) Many blood capillaries. -Generate ATP by the aerobic system, hence the term oxidative fibers. -Split ATP at a slow rate. -Slow contraction velocity. -Resistant to fatigue. -Found in large numbers in postural muscles. -Needed for aerobic activities like long distance running. 2. Type II -White. -Fast glycolytic (also called fast twitch B or fatigable fibers). -Contain: a) Low myoglobin content. b) Few mitochondria. c) Few blood capillaries. d) Large amount of glycogen. -Split ATP very quickly. -Fatigue easily. -Needed for sports like sprinting.

Relate the signal-transduction process for each receptor with the tissue response

a1> Gq> PLC> IP3> Ca++ increase B1> Gs> AC> increase cAMP> Ca++ increase; If-channel B2> Gs> AC> increase cAMP> Ca++ decrease M2> Gi> AC> decrease cAMP or Gbg> K-channels M3> Gq> PLC> IP3> Ca++ increase N1> ligand-gated Na-K channel N2> ligand-gated Na-channel Flow chart legend: PLC = phospholipase C AC = adenylyl cyclase IP3 = inositol tris-phosphate cAMP = cyclic adenosine monophosphate If = "funny" channels that conduct Na