Graded Potentials, AP, and Synaptic Transmission

Know the types of propagation of action potentials

*Contiguous conduction*: (one next to another) conduction in unmyelinated fibers; action potentials spread along every portion of the membrane *Saltatory conduction*: rapid conduction in myelinated fibers; impulse jumps over sections of fibers covered with insulated myelin -Saltatory is about 50 times as fast because of the myelinated fibers

Understand the processes for modulation of synaptic transmission via physiological and pharmacological means

*Physiological modulation* - The normal regulation of synaptic transmission. That is, the postsynaptic potentials can be quite variable in magnitude due to a number of pre-synaptic and postsynaptic factors that can be altered. Note that while post-synaptic modulation does occur, presynaptic modulation is much more common. (Presynaptic facilitation or inhibition usually) *Drug modulation* - Essentially every step in the normal process of synaptic transmission can be altered by some drug. These processes are the most important sites of action for most neurologically active drugs. A large number of relatively specific receptor agonists and receptor antagonists exist.

Generation of AP summary

*Step 1: Resting State* -Voltage-gated Na+ and K+ channels are closed -Leakage accounts for all movement of Na+ and K+ *Step 2: Depolarization* -At threshold ALL voltage-gated channel gates (both Na+ and K+) are triggered or activated -Activation gates of voltage-gated Na+ channels open quickly -More voltage-gated Na+ channels open by positive feedback mechanism -Na+ ions rush into cytoplasm causing rapid depolarization -Inner membrane changes from negative to positive *Step 3: Repolarization* -At peak (+30 mV) Na+ inactivation gates close (Na+ channel inactivation) and K+ channels open. -Na+ channels begin to reset to resting conformation when membrane reaches normal resting potential (-70 mV). -K+ channels begin to close (delayed closing) when membrane reaches normal resting potential (-70 mV). *Step 4: Hyperpolarization* -K+ channels finish closing after membrane is hyperpolarized to -80mV and returns back to resting; while almost all Na+ channels are reset to resting conformation. -Then the Na+ K+ pump restores resting conditions

A neuron can terminate on what?

-Another neuron: a synapse -A muscle (neuromuscular junction) -A gland -Motorneurons innervate muscle fibers

Elevated plasma K+ levels (hyperkalemia) can cause?

-Causes depolarization of skeletal muscles -Initially, spontaneous action potentials occur, since the RMP is closer to threshold. -As depolarization becomes more marked, voltage-gated Na+ channels begin to inactivate (causing paralysis) (unable to fire AP)

What determines the speed of conduction

-Diameter of the fiber (larger the faster) -Myelination: lipid insulator greatly increases the conduction velocity by decreasing the capacitance & restricting AP generation to the Node of Ranvier

Describe the characteristics, permeability changes and ionic basis of graded potentials and action potentials

-Electrical signals are produced by changes in ion movement across the plasma membrane -Changes in ion movements are produce by changes in membrane permeability in response to triggering events (change in electrical field, interaction with chemical messenger, stimulus, leaky channels causing imbalance. -Membrane permeability changes are due to the activation of membrane channels

Describe the principles that govern the refractory period, the phenomena of accommodation and saltatory conduction

-Ensures one way propagation of the action potential -Limits the frequency of Action potentials -*Absolute Refractory period*: interval during which NO stimulus can elicit an action potential; most Na+ gated sodium channels are inactivated -*Relative Refractory Period*: interval when a Supranormal stimulus is required to elicit an action potential. Due to elevated gK (conductance of K+ channels) coupled with the residual inactivation of voltage-gated Na+ channels

Describe the process of summation of graded potentials (Temporal and spatial)

-There are two types of synapses: *EPSP*: excitatory postsynaptic potential (Na inward, depolarization) *IPSP*: inhibitory postsynaptic potential (K+ outward, hyperpolarization) GPSP: summation of all the EPSPs and IPSPs occurring at approximately the same time The postsynaptic neuron can be brought to threshold in two ways: -*Temporal summation*: summation of several EPSPs occurring very close together in time by successive firing of a *single presynaptic neuron* -*Spatial Summation*: summation of several EPSPs occurring simultaneously from several different presynaptic inputs -Slide 20 for picture Only if an excitatory presynaptic signal is reinforced by other supporting signals through summation will the information be passed on. Interaction of EPSPs and IPSPs allows a fine degree of discrimination and control in determining what information will pass on.

Describe how neurotransmitters are synthesized, eliminated from the synaptic cleft, and recycled

1. Vesicle and peptide neurotransmitter precursors and enzymes are synthesized in the cell and released from the Golgi 2. Vesicles travel through the axon on microtubule tracks via fast axonal transport 3. A non-peptide neurotransmitter is synthesized in the nerve terminal and transported into a vesicle 4. Vesicles are tagged with synaptotagmin that senses an increase in Ca2+ concentration and binds to the SNARE proteins on the plasma membrane to initiate exocytosis 5. After the contents of the vesicle are released, the vesicle is endocytosed back into the cell and then the vesicle along with the SNAREs are recycled

Voltage gated channel inactivation

A change in the threshold of an excitable membrane in which depolarization is prolonged or held for a long time Continuous depolarization allows some of the voltage-gated Na+ channels to inactivate. Thus, even though the membrane is depolarized, not enough Na+ channels are available to initiate an action potential.

How is an action potential initiated?

A graded depolarization must reach the axon hillock and be large enough 10 to 15mV to change the membrane potential from resting (-70mV) to threshold (-60 to -55) The axon hillock is the critical decision point because it contains the highest concentration of voltage-gated Na+ channels

Describe the process by which voltage-gated channels operate during action potentials

Action potentials take place as a result of a triggered opening and subsequent closing of two specific channels: -*Voltage-gated Na+ channels* -Has two gates: -Activation gate -inactivation gate -*Voltage-gated K+ channels* -Has only one gate which can be either open or closed -ALL voltage-gated channel gates are triggered to respond at threshold -SLIDE 29 -Na+ and K+ channels closed at first, at threshold, Na+ channel opens quickly and closes slowly and is inactivated at peak of AP. K+ channels are triggered to open at threshold and open slowly. At peak of AP, K+ channel gate open and activated. Once threshold line is crossed during repolarization, all channels are triggered to reset to initial conditions

Action Potentials

Brief, rapid, large (100mV) changes in membrane potential during which potential actually reverses -Involves only a small portion of the total excitable cell membrane -One-way propagation (unlike graded potentials) -All or none phenomenon -Stereotypical size and shape spike firing -Action potential = spike = firing

Know the terminology of excitable cells as applied to graded and action potentials (polarization, depolarization, repolarization, hyper polarization)

Graded Potentials: transient electrical signals that travel a short distance Action Potentials: self-replicating transient electrical signals that travel long distances Polarization: Any state when the membrane potential is other than 0mV Depolarization: membrane becomes less polarized than at resting potential Repolarization: membrane returns to resting potential after being depolarized Hyperpolarization: membrane becomes more polarized than at resting potential

Describe, compare and contrast the basic characteristics of graded and action potentials

Graded potentials (local potentials) occur in the receptive (dendrites & cell bodies) due to opening of chemically gated channels that allow small ion amounts to cross the membrane and the altered charge may result in a change in polarization. Degree of change depends on how many molecules make it through and decreases intensity over distance-usually only lasting a short time. Action potentials (AP) are the result of voltage gated channels opening (not chemically gated ones like GP's) and require a threshold value to be reached. Voltage below this is not sufficient to create an AP but once the threshold value is reached a temporary reversal of polarity across the plasma membrane occurs. AP's are self propagated or transmitted and maintain intensity along the synaptic knob because of the successive opening of other voltage gated channels. AP's obey the "all or none" law but not all APs have the same intensity under the same conditions.

Describe graded potentials and the process to create one

Graded potentials vary in amplitude and duration. However, the magnitude of the grated potential is related to the magnitude of the triggering event. *Step 1*: resting membrane exposed to chemical stimulus (often a neurotransmitter in synapse) -> chemically gated channels open -> membrane potential changes (depolarization or hyperpolarization) *Step 2*: Movement of ions through the channel produces local current -> this depolarizes (or hyperpolarizes) the nearby regions of the membrane. Change in potential is proportional to the stimulus (this is VERY different from AP) Graded potentials can lead to AP.

Does stimulus intensity affect the action potential?

If a stimulus exceeds threshold, an action potential will be initiated. Action potentials will always be the same for a particular axon NO MATTER HOW LARGE THE STIMULUS -ALL OR NONE -A larger stimulus may cause faster frequency of APs but will never affect magnitude

In saltatory conduction, where are the Na+ and K+ voltage gated channels?

In the Node of Ranvier in between the myelin sheaths

What is Multiple Sclerosis?

Multiple sclerosis is the most common demyelinating disease of the CNS

Compare and contrast neurotransmitters and neuropeptides

Neurotransmitters: small rapid acting molecules, synthesized in axon terminal (clear vesicle) -same neurotransmitter is always released at the particular synapse; same response happens once it binds its receptor -Quickly removed from the synaptic cleft Ex. epinephrine, norepinephrine, dopamine (tyrosine derivatives) Neuropeptides: large molecules -Synthesized in neuronal cell body (dense core vesicles) -exhibit a slow constant response by acting on adjacent neurons at lower concentrations -*Neuromodulators*- bring about long-term changes but do not cause IPSPs or EPSPs (Slide 69)

Examples of graded potentials

Postsynaptic potentials End-plate potentials Pacemaker potentials Slow-wave potentials

Understand the difference between inotropic receptors and metabotropic receptors

Receptors that are ion channels are known as ionotropic receptors (ex. muscle contraction), and receptors coupled to G proteins are called metabotropic receptors (ex. decrease in heart rate)

Describe and understand excitation-secretion coupling in chemical synapses

Step 1: An action potential, which involves voltage-gated Na+ and K+ channels, arrives at the presynaptic nerve terminal. Step 2: Depolarization opens voltage-gated Ca2+ channels, which allows Ca2+ to enter the presynaptic terminal. Step 3: The increase in intracellular Ca2+ concentration ([Ca2+] triggers the fusion of synaptic vesicles with the presynaptic membrane. As a result, packets (quanta) of transmitter molecules are released into the synaptic cleft. Step 4: The transmitter molecules diffuse across the synaptic cleft and bind to specific receptors on the membrane of the postsynaptic cell. Step 6: The binding of transmitter activates the receptor, which in turn activates the postsynaptic cell. Step 7: The process is terminated by (1) enzymatic destruction of the transmitter (e.g., hydrolysis of ACh by acetylcholinesterase), (2) uptake of transmitter into the presynaptic nerve terminal or into other cells by Na+-dependent transport systems, or (3) diffusion of the transmitter molecules away from the synapse.

Tetrodotoxin (TTX)

Topical lidocaine: local anesthetic -Both inhibit voltage-gated Na+ channels, preventing the occurrence of action -potentials.

Compare and contrast electrical and chemical synapses

Two types of synapses: excitatory synapses and inhibitory synapses Electrical: gap junctions *Chemical*: (more common) -either excitatory or inhibitory -not touching the post-synaptic neuron -slower than gap junction because of synapse space(synaptic delay)