Action Potential: Ionic Mechanisms

Abstract

The generation and propagation of the action potential require sodium influx via voltage‐dependent sodium channels that drive the upstroke of the action potential. This positive feedback cycle is terminated by sodium channel inactivation that shuts down the channel at depolarised membrane potentials. The reduced sodium influx along with increased potassium efflux permits rapid action potential repolarisation. 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 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 depolarises 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 depolarised.
  • The reduction of sodium influx resulting from inactivation combined with potassium efflux from the cell via voltage‐dependent and/or voltage‐independent potassium channels drive the repolarisation phase of the action potential.
  • The voltage‐dependent potassium channels often remain active following the action potential (slow to close) to generate an afterhyperpolarization (AHP).
  • The AHP can speed sodium channel recovery from inactivation, which is faster at more hyperpolarised 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 vs. 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; Hodgkin and Huxley; squid giant axon; threshold refractory period; unmyelinated axon; myelinated axon; 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. (b) A diagram of the positive feedback cycle that drives the depolarisation phase of the action potential. Depolarisation leads to sodium channel activation, which leads to sodium influx and further depolarisation.
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. (b) The isolated sodium current peaks in less than a millisecond and then rapidly inactivates. (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. (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 depolarises the neurons beyond threshold to discharge a single action potential. (c) A suprathreshold current injection sufficiently depolarises the neuron that multiple action potentials are generated during the 400‐ms injection.
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 constants 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. (a) Shows the simulated action potential and the (b) show simulated sodium (GNa) and potassium (GK) conductances during the action potential. Note the relative activation speeds of the two conductances. Courtesy of Dr Stephen W Jones, Case Western Reserve University.
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References

Aldrich RW, Corey DP and Stevens CF (1983) A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature 306: 436–441.

Bernstein J (1912) Elecktrobiologie. Vieweg: Braunschweig.

Bialer M, Johannessen SI, Levy RH, et al. (2009) Progress report on new antiepileptic drugs: a summary of the ninth Eilat conference (EILAT IX). Epilepsy Research 83: 1–43.

Catterall WA, Goldin AL and Waxman SG (2005) International Union of Pharmacology. XLVII. Nomenclature and structure‐function relationships of voltage‐gated sodium channels. Pharmacological Reviews 57: 397–409.

Chiu SY, Ritchie JM, Rogart RB and Stagg D (1979) A quantitative description of membrane currents in rabbit myelinated nerve. Journal of Physiology (London) 292: 149–166.

Chiu SY and Ritchie JM (1980) Potassium channels in nodal and internodal axonal membrane of mammalian myelinated fibres. Nature 284: 170–171.

Devaux J, Alcaraz G, Grinspan J, et al. (2003) Kv3.1b is a novel component of CNS nodes. Journal of Neuroscience 23: 4509–4518.

Devaux JJ, Kleopa KA, Cooper EC and Scherer SS (2004) KCNQ2 is a nodal K+ channel. Journal of Neuroscience 24: 1236–1244.

Erisir A, Lau D, Rudy B, et al. (1999) Function of specific K(+) channels in sustained high‐frequency firing of fast‐spiking neocortical interneurons. Journal of Neurophysiology 82: 2476–2489.

Grissmer S, Nguyen AN, Alyar J, et al. (1994) Pharmacological characterization of five cloned voltage‐gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Molecular Pharmacology 45: 1227–1234.

Gutman GA, Chandy KG, Grissmer S, et al. (2005) International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage‐gated potassium channels. Pharmacological Reviews 2005, 57: 473–508.

Hamill OP, Marty A, Neher E, Sakmann B and Sigworth FJ (1981) Improved patch‐clamp techniques for high‐resolution current recording from cells and cell‐free membrane patches. Pflügers Archiv 391: 85–100.

Hodgkin AL and Huxley AF (1939) Action potentials recorded from inside a nerve fibre. Nature 144: 710–711.

Hodgkin AL and Katz B (1949) The effect of sodium ions on the electrical activity of the giant axon of the squid. Journal of Physiology (London) 108: 37–77.

Hodgkin AL, Huxley AF and Katz B (1952) Measurement of current–voltage relations in the membrane of the giant axon of Loligo. Journal of Physiology (London) 116: 424–448.

Hodgkin AL and Huxley AF (1952a) Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. Journal of Physiology (London) 116: 449–472.

Hodgkin AL and Huxley AF (1952b) The components of membrane conductance in the giant axon of Loligo. Journal of Physiology (London) 116: 473–496.

Hodgkin AL and Huxley AF (1952c) The dual effect off membrane potential on sodium conductance in the giant axon of Loligo. Journal of Physiology (London) 116: 497–506.

Hodgkin AL and Huxley AF (1952d) A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal of Physiology (London) 117: 500–544.

Kaczmarek LK and Zhang Y (2017) KV3 channels: enablers of rapid firing, neurotransmitter release, and neuronal endurance. Physiological Reviews 97: 1431–1468.

Kole MHP, Ilschner SU, Kampa BM, et al. (2008) Action potential generation requires a high sodium channel density in the axon initial segment. Nature Neuroscience 11: 178–186.

Maljevic S, Wuttke TV and Lerche H (2008) Nervous system Kv7 disorders: breakdown of a subthreshold break. Journal of Physiology (London) 586: 1791–1801.

Pan Z, Kao T, Horvath Z, et al. (2006) A common ankyrin‐Gbased mechanism retains KCNQ and NaV channels at electrically active domains of the axon. Journal of Neuroscience 26: 2599–2613.

Rush AM, Cummins TR and Waxman SG (2007) Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. Journal of Physiology (London) 579: 1–14.

Schwarz JR, Glassmeier G, Cooper EC, et al. (2006) KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. Journal of Physiology (London) 573: 17–34.

Vacher H, Mohapatra DP and Trimmer JS (2008) Localization and targeting of voltage‐dependent ion channels in mammalian central neurons. Physiological Reviews 88: 1407–1447.

Waxman SG and Ritchie JM (1985) Organization of ion channels in the myelinated nerve fiber. Science 228: 1502–1507.

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. Sinauer Associates: Sunderland, MA.

Levitan IB and Kaczmarek LK (2015) The Neuron: Cell and Molecular Biology, 4rd edn. Oxford University Press: New York.

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

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Elmslie, Keith S(Nov 2019) Action Potential: Ionic Mechanisms. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000002.pub3]