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GENERATION OF NERVE ACTION POTENTIAL (Lectures 7 & 8) Learning Objectives:

1. Compare electrotonic potentials and action potentials.

2. Describe each phase of the nerve action potential.

3. Explain the underlying ionic conductances responsible for the action potential.

4. Describe the gating mechanisms of the voltage-gated channels involved in the

action potential.

5. Define absolute refractory period, relative refractory period, and accommodation. Reading Assignment: Medical Physiology, 13th ed., Guyton and Hall, pages 65-69, 72-73.

Lecture Topic Outline:

Comparison of Electrotonic Potentials and Action Potentials

Generation of the Action Potential

o Characteristics of the action potential o Ionic mechanisms underlying the action potential o Measurement of action potential conductances o Separation of ionic conductances underlying the action potential o Ion channel activity during the action potential

Properties of action potentials

Supplemental Lecture Material:

• Comparison of Electrotonic and Action Potentials

Electrotonic Potentials Action Potentials

Threshold No Yes Conduction Passive, decremental Active, all-or-none Size Graded, stimulus intensity-

dependent

All-or-none Stimulus Chemical, mechanical Electrical Polarity INSIDE NEGATIVE INSIDE POSITIVE Other features Not self-regenerating Self-regenerating Does not propagate Propagates No refractory period Refractory period Temporal summation No temporal

summation Spatial summation No spatial summation

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Generation of the Action Potential

o Action potentials are electrical impulses transmitted by nerve and muscle cells.

They can be thought of as a change in the voltage of the membrane potential

that causes it to go from its negative resting state to a positive value for a very

brief time.

o An action potential is a change in the voltage of the membrane potential that

causes it to go from its negative resting state to a positive value for a very brief

time.

o The membrane switches from its state of being highly permeable to K+ ions at

rest to being highly permeable to Na+ at the peak of the action potential.

o Characteristics of the action potential

• Resting Level

At rest, the membrane is most permeable to K+. RMP is close to the

equilibrium potential for K+.

• Threshold Threshold is reached when the membrane is depolarized by some electrical, mechanical or chemical stimulus causing an influx of positively charged ions. At threshold, voltage-gated Na+ channels are actively recruited to gate open and further depolarize the membrane.

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• Rising phase The membrane become more permeable to Na+ as a critical number of voltage-gated Na+ continue to gate open as a result of a positive feedback mechanism.

• Overshoot

The membrane potential becomes so depolarized that it overshoots and is

reversed in polarity. This is the phase in which the membrane is most permeable

to Na+

ions and approaches the equilibrium potential for Na+.

• Peak

At or near the peak of the action potential Na+ permeability begins to

decrease and K+ permeability through voltage-gated K+ channels increases.

• Repolarization

The change in membrane conductance again drives the membrane potential

toward EK, accounting for repolarization of the membrane.

• Afterhyperpolarization (=Positive afterpotential)

The afterhyperpolarization is a result of K+

channels remaining open, thus

allowing the continued efflux of K+ ions.

o Ionic mechanisms underlying the action potential • Increase in gNa - The depolarization and rising phase of the action potential

can be attributed to the increase in Na+ conductance.

• Decrease in gNa and increase in gK - The repolarization phase can be

attributed to both the decrease in Na+ conductance and the slower increase

in K+ conductance.

• Decrease in gK - While the after-hyperpolarization is due to the sustained

increase of K+ conductance, K+ conductance decreases eventually to return

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the membrane potential to resting levels.

o Measurement of action potential conductances - Voltage-clamp technique

- Much of the information about the conductances underlying the action

potential was obtained using the voltage-clamp technique. This electronic

technique allows one to hold the membrane potential constant in a muscle

or nerve and measure the ionic current that flows across the membrane.

Single Na+ Channel Currents

Averaged Single Na+ Channel Currents

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o Separation of ionic conductances underlying the action potential - Pharmacological tools have been used to determine the underlying ionic

mechanisms of the initiation and repolarization phases of the action

potential. Tetrodotoxin (TTX) blocks voltage-dependent Na+

conductance (permeability) and tetraethylammonium (TEA) blocks

voltage- dependent K+

conductance (permeability).

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Gating Mechanisms Underlying Action Potential Ion channel activity during the action potential

Mechanism of the voltage-sensitive Na+ channel Resting state

Activation state

Inactivation state

Conductance States of Voltage-Sensitive Na+ Channel

Mechanism of the voltage-sensitive K+ channel

Resting state

Slow activation state

Conductance States of Voltage-Sensitive K+ Channel

+Saxitoxin (STX)

Activation Gate Inactivation Gate

Activation Gate

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Time-course of ion channel activity during action potential

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Gating Mechanisms Underlying Action Potential

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Properties of action potentials

o Propagated without decrement

o All-or-none response

o Voltage inactivation of the action potential

o Refractory periods

o Absolute refractory period The timeframe in which sodium channels have not totally reset to their

resting state and cannot be gated open again. This period limits the

rate of firing of action potentials. It also prevents action potentials

from traveling backward along the axon, because the region of the axon

that has just produced the action potential is refractory. o Relative refractory period The neuron enters a phase in which it will generate another action

potential if a stronger-than-normal stimulus is applied to the neuron.

Some portion of the voltage-gated sodium channels have reset and are

available for opening.

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o Accommodation

Explosive depolarization of the action potential can occur only if a critical

number of Na+ channels are recruited. However, when a nerve is

depolarized slowly (eg., hyperkalemia – chronic elevated blood potassium

levels), the normal threshold may be passed without an action potential

being fired; this phenomenon is called accommodation. Na+ and K+

channels are both involved in accommodation. If the depolarization is slow

enough, the critical number of open Na+ channels required to trigger the

action potential may never be attained because of inactivation of the

voltage-gated Na+ channels. In addition, K+ channels open slowly in

response to the depolarization. The increased gK tends to oppose

depolarization of the membrane, thus, making it still less likely to fire an

action potential.