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True or false: The characteristics of action potentials are exactly the same from tissue to tissue.

False. They vary. An AP in cardiac muscle looks different than in skeletal muscle. see slide 4 of notes


Action potentials are initiated by membrane ______ which causes the opening of certain voltage dependent ionic channels. Discus what types of channels open in nerve, skeletal, cardiac muscle, SA node, AV node, and smooth muscle cells.

1. depolarization

2. in nerves, skeletal muscle,and cardiac muscle membrane depolarization causes the opening of voltage gated Na+ channels (produces "upstroke" of AP). For SA node, AV node, and smooth muscle voltage gated Ca+ channels produce membrane depolarization


What voltage gated channels cause repolarization of the membrane in nerve and skeletal muscle?

Caused by inactivation of Na+ channels and opening of voltage-gated K+ channels. Note that Na+ channel inactivation involves a different gate and that once this inactivation gate is closed, it does not reopen until the membrane potential returns to or close to resting level. K+ channels are also activated by depolarization but they open more gradually (noticed at peak of AP)


What are some generic characteristics of APs?

1. all-or-none

2. non-decremental (amplitude and duration of AP do not change as it is transmitted)

3. propagation

4. unidirectional

5. refractory periods (absolute and relative) refractory periods are major reason for unidirectional propagation. a region that has just undergone an AP cannot produce another AP

6. threshold: threshold potenial is potenial at which an AP will be initated. is not a standard unvarying value


How do voltage-gated Na+ channels work? Discuss their gate(s) and the probability of their openness. 

voltage-gated Na+ channels have an activation gate and an inactivation gate. At resting Vm, the activation gate is closed and the inactivation gate is open. During an AP when the membrane is depolarized, both gates are transiently open to allow for Na+ flux. The activation gate opens rapidly and after a few msec, the inactivation gate closes (closes more slowly). The closure of the inactivation gate is visualized as the peak of the AP when Na+ ions can no longer flow into the cell. (note: resting is -90 mV in cardiac and skeletal muscle and is -70 mV i.e. more depolarized in neurons)

The probability of a gate moving as well as the time required for it to move are functions of membrane potential. The probability that the activation gate will open is a function of membrane potential only. The probability of an inactivation gate being open is dependent on the fraction of Na+ channels that are available to open as a function of membrane potential.

At any point in time, a channel is either completely open or completely closed. When looking at many channels in a tissue, the probability that a channel will be activated or inactivated is more important. 

There are 2 ways to close a Na+ channel: closure of the inactivation gate which occurs when the membrane is depolarized and closure of the activation gate which occurs when the membrane is repolarized.

when activation gate is close: deactivation

activation gate open: activation

inactivation gate close: inactivation

Opening of voltage gated Na+ channels drives Vm toward ENa+ (which is +60 mV) but does not quite get there (~+50mV)


How do voltage-gated K+ channels work? Discuss their gate(s) and the probability of their openness. 

Note: Only discussing K+ channels in nerve and skeletal muscle

voltage-gated K+ channels only have an activation gate. This activation gate opens when the membrane is depolarized, but, on average, it opens more slowly than does the activation gate of the Na+ channel AND more depolarization is needed to open the gate. This can be seen at peak of AP when K+ flux is the most appreciable at time when voltage-gated Na+ channels have been inactivated. voltage-gated K+ channels also close more slowly than Na+ channels (K+ channels take 5 msec to close after returning to resting Vm while Na+ channels take less than one msec. reason for hyperpolarization seen in an AP: membrane potential more negative than resting). The voltage gated K+ channel does not have an inactivation gate bc once opened under physiological conditions by depolarization, it has the tendency to turn itself off due to the movement of Vm toward EK (which is about -95 mV)

Probablity of openness increases with membrane depolarization


To elicit an AP, the membrane must first be ___ by a sufficent amount.



Discuss the positive feedback cycle of membrane depolarization as it pertains to Na+ channels and what causes this loop to cease. 

As the membrane becomes depolarized, voltage gated Na+ channels open allowing inward flow (negative current by convention) of Na+. This causes further membrane depolarization as each Na+ ion drives Vm closer to ENa (+60 mV). Further membrane depolarization allow for even more Na+ current which causes this feedback loop. The positive feedback (self-sustaining process) leads to upstroke of AP but ceases when Na+ channel inactivate (due to closing of inactivation gate, a time dependent process). As voltage-gated K+ channels activate and allow for K+ efflux (positive current by convention) it drives membrane potential closer to EK

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Discuss the depolarizing after potential in skeletal muscle and the reason this is observed.

During this period immediately following the action potential proper, the membrane potential is somewhat less negative than the resting potential. This is primarly caused by the T-tubule system which has a slower and more prolonged AP; in addition, due to its very small diameter but large overall surface area, there can be transient K+ accumulation in the T tubule system lumen

(hyperpolarization period seen in nerves)


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Discuss the effect of hyperkalemia on membrane potential and why this is dangerous.

Hyperkalemia causes Vm to be less negative (more positive) than resting Vm. If Vm is too high, voltage-gated Na+ channels cannot be stimulated and an AP can't be generated.


Discuss the concepts of absolute and relative refractory periods and the reasons they exist. 

During the absolute refractory period, it is impossible to stimulate another AP because essentially all voltage-gated Na+ channels are inactivated and will stay inactivated until Vm returns approximately to resting level. During hyperpolarization (caused by elevation of K+ permeability due to slow closing of voltage-gated K+ channels), there is a relative refractory period during which it is relatively more difficult to stimulate an AP

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Threshold is the membrane potential at which enough voltage-gated Na+ channels have been opened that the process of membrane depoalriation becomes self-sustaining. Discuss how threshold can be changed.

1. Permeability of K+ and Cl- at rest affect threshold. The higher the permeability to these ions, the more depolarized the threshold potential. In inhibitory synapses in neurons, the permabilities of these ions change. 

2. The number of voltage-gated Na+ channels available. The more Na+ channels available, the smaller the depolarization needed to reach threshold. Similarly, if less Na+ channles are available (as can occur as the result of some toxins and a variey of drugs such as local anesthetics) then threshold will be at more depolarized potential (making it harder to fire an AP)


Discuss the concept of resting inactivation and how it affects threshold. 

The rate at which the membrane depolarizes can also influence threshold. In order to be effective in initating an AP the membrane must be depolarized rapidly (over a period of a few msec to a few tens of msec). If the membrane depolarizes gradually it may never produc e an AP at all. This is due to inactivation of Na+ channels which is referred to as resting inactivation. If a membrane is depolarized incrementally, say by 1 mV/second, the Na+ channels that initially were activated will be deactivated by the time the membrane slightly depolarizes in the next second. This results in a gradual decrease in the number of Na+ channels available to be activated. Is of clinical importance in diseases such as hyperkalemia or ischemic heart disease. In gradual development of hyperkalemia, can get gradual membrane depolarization that results in resting inactivation.


What are subthreshold potentials?

changes in membrane potential that do not reach threshold. physiological examples include some synaptic potentials. in CNS, it is necessary for many excitatory synapses to be active simultaneously to generate a potential sufficient enough to reach threshold. Subthreshold potentials spread decrementally from their site of origin i.e the potential decreases progressively decreases with distance away from the origin


True or false: As an AP propagates down a neuron, the AP occurs at a different time for each location, but the amplitude and duration are the same at each location under normal circumstances.



What factors influence AP propagation and how?

1. cell fiber/diamerter. the larger the diameter of a fiber, the more rapid the AP propagation. reason for relatively large sizes of neurons and muscles. increasing cell diameter increases the ratio of cross-sectional ara to membrane surface area. the increased cross sectional area decreases longitudinal resistance of the cell. Although capacitance increases with membrane area (and larger cells have a larger membrane area), the cross-sectional area increases more and therefore the net effect is increased speed of propagation.

2. resting membrane resistance Ri. The higher the resistance of the membrane (the fewer channels open at rest) the faster will be AP propagation. Recall that open K+ channels are the primary factor which hold the membrane at resting potential (Cl- channels also do this). When we speak of high resistance here, we really mean low conductance i.e. low permeability to K+ and/or other ions which may tend to resist a change in voltage

3. Intracellular longitudinal resistance (Ri). is a measure of how easily cytoplasm conducts electrical current. does not vary to any significant extent in body but when dealing with electrially coupled cells (myocytes, smooth muscle) Ri can vary significantly. The lower Ri, the more rapid the propagation of the AP

4. Number of voltage gated Na+ channels. the higher the density of these channels, the faster the speed of AP propagation. is similarly true for Ca2+ channels which cause membrane depolarization in SA and AV node cells. 

5. Membrane capacitance (Cm). the lower the membrane capacitance, the faster the conduction velocity of an AP. This does not vary from cell to cell, however, myelin can effectively reduce capacitance significantly


What is the length constant?

Subthreshold potentials decrease in amplitude as they spread from their site of origin. The length constant quantifies this decrement and defines the factors which determine how rapidly (as a function of distance) it occurs. The length constant is denoted by lambda and at any distance, x, from the site of origin of a subthreshold potential, (Vx for the potential at site x) is given by:

Vx=Vmax exp(-x/lambda) where Vmax is max potential at site of origin. 

At a distance lambda from the site of origin, the membrane potential will have fallen to 37% of its max value. lambda=(aRm/2Ri)½ where a is fiber diameter, Rm is membrane resistance, and Ri is resistance of cytoplasm. The length constant becomes larger as cell diameter and membrane resistance increases and becomes smaller with resistance of cytoplasm. The larger the length constant, the faster an AP will propagate

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How does myelin affect AP propagation?

remember that internodes are myelinated portions of axons and nodes of Ranvier are non-myelinated and are where Na+ and K+ voltage gated channels are concentrated

Myelin effectively increases axonal membrane resistance and decreases its effective capacitance in the internodal region. This means that a smaller amount of charge at a node of Ranvier undergoing an AP can go a longer way toward depolarizing neighboring regions of membrane. Only at nodes of Ranvier do any significant changes in membrane permeability and ion flux/current take place. Internodal regions are very well insulated and contain few to no voltage gated channels. This results in discontinuous or saltatory AP as the AP jumps from node ot node. This speeds AP conduction velocity and decreases the number of Na+ and K+ ions that must cross the membrane (thus saving long term energy expenditure by the Na/K pump)

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What is electromyography and how does it work?

EMGs are measurements of potential outside of a cell. Remember that during an AP, the membrane depolarizes and there is more positive charge inside than outside of the cell. A muscle cell at rest will have no electrical activity and an EMG will give a flat reading. During activity, APs are generated and an EMG detects changes in membrane potential as measured extracellularly (can be placed intramuscularly within the extracellular space or on skin). As strength of contraction increases, more fibers are recruited and the signal becomes stronger. EMGs allow measurement of amplitude and number of muscle depolarizations that give diagnostic clues for a number of myopathies and neuropathies

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