Sodium Channels

Abstract

Excitable cells, such as neurons or cardiomyocytes, communicate with each other via action potentials. This fast change in membrane voltage is initiated by the rapid opening of voltage‐gated sodium selective channels, of which to date nine subtypes are known (Nav1.1–Nav1.9). These large membrane spanning proteins undergo gating changes on a timescale ranging from milliseconds to minutes. Depolarization past threshold leads to activation and sodium ions flow into the cell. Within milliseconds the inactivation particle blocks the pore, current flow is interrupted and the channel is fast inactivated. Channels need to recover from fast inactivation at negative potentials to be able to reopen anew.

Recent data on crystal structures shape our 3D picture of sodium channels and mutagenesis studies help understanding their structure–function relation. Sodium channels are major regulators of membrane excitability and play an important role in pain, arrhythmias and muscle diseases, and subtype‐specific blockers have been currently developed.

Key Concepts

  • The fast upstroke of the action potential (AP) is initiated by the opening of voltage‐gated sodium channels (Navs).

  • Navs are large transmembrane proteins consisting of four homologous domains (DI–DIV).

  • Each domain consists of six transmembrane segments S1–S6, which form a voltage sensor (S1–S4) and parts of the pore module (S5–S6).

  • The domains are connected by intracellular linkers. The DIII–DIV linker contains the inactivation particle.

  • Upon depolarization, Navs open quickly, sodium ions flow into the cell, and within milliseconds, fast inactivation occurs.

  • Slow inactivation happens on a much slower timescale (seconds to minutes) and involves other parts of the channel protein.

  • Recently, crystal structures of bacterial sodium channels have helped explicate the changes in 3D structure that accompany gating.

  • Navs are involved in the generation of pain, arrhythmias and myopathies (among others).

Keywords: excitability; ion channels; membrane protein; resting potential; pain

Figure 1. Schematic view of the structure of voltage‐gated sodium channels. (a) Side view: The pore‐forming α‐subunit of Navs is composed of 24 transmembranal α‐helices that are organized in four domains (DI–DIV). The inactivation particle is formed by the IFMT motif in the linker between DIII and DIV. (b) Enlargement of one domain, indicating the position of the S4–S5 linker and the putative pore helices. The S4 of each domain carries the gating charges. (c) Top view: The Nav pore module is built by the S5 and S6 of each domain (blue circle around the pore). It is surrounded by the voltage‐sensing domains (VSDs) shown in green. (d) Side view into the pore module of a closed Nav. Only two domains are shown with their S5 and S6 segments in blue (they form part of the pore module) and their VSDs. The intracellular interaction of the S6 prevents ions from permeating. (e) Side view into the pore module of an activated Nav. Owing to the movement of the VSDs, the S6 of the four domains splay apart and sodium ions may flow into the cell.
Figure 2. Ionic currents through Navs. (a) Whole cell patch clamp recordings from HEK cells expressing Nav1.7, which was subjected to the indicated voltage protocol (upper part). Upon the stepwise depolarization, Navs quickly activate (as indicated by the scheme in the lower part), and Na+ enters the cell, resulting in the shown current traces. (b) Current–voltage relation of the recorded cell (current is shown relative to the maximal inward current). Navs open at their activation threshold and the plotted declines, when the potential approaches the Nernst potential for Na+. (c) Within milliseconds following activation, Navs fast inactivate. During this process, the inactivation particle, which is formed by the amino acids IFMT in the intracellular linker between DIII and DIV, enters the open pore and prevents ions from flowing.
Figure 3. Nav gating scheme and resurgent currents. (a) Simple gating scheme to describe the transitions between several closed states (C −1 to C ), the open state (O), the fast or slow inactivated state (Ifast/slow, for reasons of simplicity, only one inactivated state is shown) and the state of open‐channel block (B). The names of the transitions between these states can be read from the arrows. (b) Whole‐cell recordings of Nav current from a transfected HEK cell showing resurgent currents that were evoked by the indicated protocol. The lower part shows the schematic concept of the open‐channel block that is thought to underlay resurgent currents.
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Further Reading

Ruben PA (ed) (2014) Voltage Gated Sodium Channels. Handbook of Experimental Pharmacology, vol. 221. ISBN 978-3-642-41587-6, Berlin, Heidelberg: Springer.

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

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Lampert, Angelika, Stühmer, Walter, and Waxman, Stephen G(Jan 2015) Sodium Channels. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000127.pub2]