Action Potential: Ionic Mechanisms

Abstract

The generation and propagation of the action potential requires sodium influx via voltage‐dependent sodium channels that drives the upstroke of the action potential. This positive feedback cycle is terminated by sodium channel inactivation that shuts down the channel at depolarized membrane potentials. The reduced sodium influx along with increased potassium efflux permits rapid action potential repolarization. The enhanced potassium efflux is mediated by the activity of both voltage‐dependent and voltage‐independent potassium channels. The recovery of sodium channels from inactivation and the slow closing of potassium channels following the action potential determine the refractory period, which is a period of increased action potential threshold. Thus, the kinetics of sodium and potassium channel gating determine not only the action potential shape and duration, but also the threshold for action potential generation.

Key concepts:

  • Sodium influx via voltage‐dependent sodium channels depolarizes the membrane to activate more sodium channels in a positive feedback mechanism that generates the ballistic rising phase of the action potential.

  • This positive feedback cycle is terminated by a separate gating process called inactivation, which shuts down sodium flux even though the membrane is still depolarized.

  • The reduction of sodium influx resulting from inactivation combined with potassium efflux from the cell via both voltage‐dependent and voltage‐independent potassium channels drive the repolarization phase of the action potential.

  • The voltage‐dependent potassium channels often remain active following the action potential (slow to close) to generate an after‐hyperpolarizing potential (AHP).

  • The AHP can speed sodium channel recovery from inactivation, which is faster at more hyperpolarized voltages, so that the channels are more rapidly reset to participate in generating the next action potential.

  • Action potential threshold is determined by the relative activity of sodium versus potassium channels with an action potential being generated if the sodium influx is larger than the potassium efflux.

  • Insulating the axon with myelin increases the speed of action potential propagation by limiting action potential generation to small unmyelinated gaps called nodes of Ranvier.

  • High‐density clustering of sodium channels at the nodes of Ranvier ensures sufficient current is generated to exceed threshold at the next node so that the action potential is faithfully propagated along the axon.

Keywords: sodium channels; potassium channels; threshold; inactivation; saltatory conduction

Figure 1.

The action potential. (a) An action potential recorded from a rat sympathetic neuron during a 400‐ms current injection. The different phases of the action potential are labelled, together with the equilibrium potentials for sodium (ENa) and potassium (EK). The threshold voltage is also marked. Unpublished data recorded by Dr Geoffrey G Schofield, Tulane University Medical School. (b) A diagram of the positive feedback cycle that drives the depolarization phase of the action potential. Depolarization leads to sodium channel activation, which leads to sodium influx and further depolarization.

Figure 2.

The sodium and potassium currents that underlie the action potential. (a) The total membrane current recorded from a sympathetic neuron in a physiological saline solution. The early inward current is carried by sodium ions and the later outward current is carried by potassium ions. Unpublished data recorded by Dr Geoffrey G Schofield. (b) The isolated sodium current peaks in less than a millisecond and then rapidly inactivates. Unpublished data recorded by the author. (c) The isolated potassium current activates slowly compared with sodium current. Note the time scale bar for the potassium current is 40 ms, whereas the bar for sodium current is 5 ms. The brief inward current at the beginning of the step is a voltage clamp artefact. Unpublished data recorded by Dr Walter Robertson, Tulane University Medical School. (d) A comparison of the voltage dependence of sodium and potassium currents in rat sympathetic neurons. Conductance at each voltage was calculated as described in the text.

Figure 3.

The effect of increasing stimulus strength on action potential generation. (a) A subthreshold current injection does not induce the neurons to discharge an action potential. (b) A larger current injection depolarizes the neurons beyond threshold to discharge a single action potential. (c) A suprathreshold current injection sufficiently depolarizes the neuron that multiple action potentials are generated during the 400‐ms injection. All unpublished sweeps recorded from a rat sympathetic neuron by Dr Geoffrey G Schofield.

Figure 4.

Voltage protocols used to measure the time course and voltage dependence of inactivation. (a) The steady‐state inactivation versus voltage relationship (h) is generated by measuring the effect of a range of conditioning potentials (−120 to −10 mV) on a test pulse current (test pulse voltage=−20 mV). The 1‐s conditioning step is sufficient for sodium channel inactivation to reach steady state at each voltage (see panel (d)). Note that ∼1/2 of the sodium channels are inactivated at the resting membrane potential. (b) The time course of inactivation and recovery from inactivation can be measured at voltages that do not activate sodium current. This envelope protocol measures the effect of changing the duration of the conditioning potential (−50 mV) on the test pulse current (−20 mV). Test pulse currents are shown for conditioning steps of 0, 75, 175 and 450 ms. The plot of current versus conditioning step duration is fitted by a single exponential function with a time constant (τ) of 120 ms. (c) The time course of recovery from inactivation can be measured using a two‐pulse protocol where the first pulse inactivates the current and the second pulse tests for recovery as the interval between the voltage steps increases. The recovery potential in this example is −80 mV, which is also the holding potential. A plot of current amplitude during the second pulse versus the step interval is fitted by a single exponential equation. (d) Time constants of inactivation and recovery from inactivation are plotted against voltage. Time courses were obtained using three different protocols: inactivation during voltage steps (◊), envelope protocol as in (b) (•) and double pulse protocol as in (c) (▪). All unpublished data recorded from rat sympathetic neurons by the author.

Figure 5.

Computer simulation of the action potential using the Hodgkin–Huxley model. The top trace shows the simulated action potential and the bottom two traces show simulated sodium (GNa) and potassium (GK) conductances during the action potential. Note the relative activation speeds of the two conductances. The simulation programme (Axovacs) was written by Dr Stephen W Jones, Case Western Reserve University.

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Further Reading

Armstrong CM and Hille B (1998) Voltage‐gated ion channels and electrical excitability. Neuron 20: 371–380.

Bean BP (2007) The action potential in mammalian central neurons. Nature Reviews. Neuroscience 8: 451–465.

Hille B (2001) Ionic Channels of Excitable Membranes, 3rd edn. Sunderland, MA: Sinauer Associates.

Levitan IB and Kaczmarek LK (2002) The Neuron: Cell and Molecular Biology, 3rd edn. New York: Oxford University Press.

Matthews GG (2002) Cellular Physiology of Nerve and Muscle, 4th edn. Boston, MA: Wiley‐Blackwell Scientific Publications.

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Elmslie, Keith S(Feb 2010) Action Potential: Ionic Mechanisms. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000002.pub2]