Sodium Channels


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.


Adsit GS, Vaidyanathan R, Galler CM, Kyle JW and Makielski JC (2013) Channelopathies from mutations in the cardiac sodium channel protein complex. Journal of Molecular and Cellular Cardiology 61: 34–43.

Burge J and Hanna M (2012) Novel insights into the pathomechanisms of skeletal muscle channelopathies. Current Neurology and Neuroscience Reports 12 (1): 62–69.

Calhoun JD and Isom LL (2014) The role of non‐pore‐forming beta subunits in physiology and pathophysiology of voltage‐gated sodium channels. Handbook of Experimental Pharmacology 221: 51–89.

Catterall WA (2014) Sodium channels, inherited epilepsy, and antiepileptic drugs. Annual Review of Pharmacology and Toxicology 54: 317–338.

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 (4): 397–409.

Chancey JH, Shockett PE and O'Reilly JP (2007) Relative resistance to slow inactivation of human cardiac Na + channel hNav1.5 is reversed by lysine or glutamine substitution at V930 in D2‐S6. American Journal of Physiology ‐ Cellular Physiology 293 (6): C1895–C1905.

Chen Y, Yu FH, Surmeier DJ, Scheuer T and Catterall WA (2006) Neuromodulation of Na + channel slow inactivation via cAMP‐dependent protein kinase and protein kinase C. Neuron 49 (3): 409–420.

Cox JJ, Reimann F, Nicholas AK, et al. (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444 (7121): 894–898.

Cummins TR, Aglieco F, Renganathan M, et al. (2001) Nav1.3 sodium channels: Rapid repriming and slow closed‐state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons. Journal of Neuroscience 21 (16): 5952–5961.

Cummins TR and Sigworth FJ (1996) Impaired slow inactivation in mutant sodium channels. Biophysical Journal 71 (1): 227–236.

Dib‐Hajj SD, Yang Y, Black JA and Waxman SG (2013) The Na(V)1.7 sodium channel: from molecule to man. Nature Review Neuroscience 14 (1): 49–62.

Eberhardt M, Nakajima J, Klinger AB, et al. (2014) Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation. Journal of Biological Chemistry 289 (4): 1971–1980.

Estacion M, Gasser A, Dib‐Hajj SD and Waxman SG (2010) A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons. Experimental Neurology 224 (2): 362–368.

Faber CG, Hoeijmakers JG, Ahn HS, et al. (2012a) Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Annals of Neurology 71 (1): 26–39.

Faber CG, Lauria G, Merkies IS, et al. (2012b) Gain‐of‐function Nav1.8 mutations in painful neuropathy. Proceedings of the National Academy of Sciences of the United States of America 109 (47): 19444–19449.

Fleidervish IA, Friedman A and Gutnick MJ (1996) Slow inactivation of Na + current and slow cumulative spike adaptation in mouse and guinea‐pig neocortical neurones in slices. Journal of Physiology 493 (Pt 1): 83–97.

Grieco TM, Malhotra JD, Chen C, Isom LL and Raman IM (2005) Open‐channel block by the cytoplasmic tail of sodium channel beta4 as a mechanism for resurgent sodium current. Neuron 45 (2): 233–244.

Hartshorne RP, Messner DJ, Coppersmith JC and Catterall WA (1982) The saxitoxin receptor of the sodium channel from rat brain. Evidence for two nonidentical beta subunits. Journal of Biological Chemistry 257 (23): 13888–13891.

Heinemann SH, Terlau H, Stuhmer W, Imoto K and Numa S (1992) Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356 (6368): 441–443.

Hille B (1977) Local anesthetics: hydrophilic and hydrophobic pathways for the drug‐receptor reaction. Journal of General Physiology 69 (4): 497–515.

Hodgkin AL and Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal of Physiology 117 (4): 500–544.

Huang J, Han C, Estacion M, et al. (2014) Gain‐of‐function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain 137 (Pt 6): 1627–1642.

Jarecki BW, Piekarz AD, Jackson JO 2nd and Cummins TR (2010) Human voltage‐gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents. Journal of Clinical Investigation 120 (1): 369–378.

Kispersky TJ, Caplan JS and Marder E (2012) Increase in sodium conductance decreases firing rate and gain in model neurons. The Journal of Neuroscience 32 (32): 10995–11004.

Kuo CC and Bean BP (1994) Na + channels must deactivate to recover from inactivation. Neuron 12 (4): 819–829.

Laezza F, Lampert A, Kozel MA, et al. (2009) FGF14 N‐terminal splice variants differentially modulate Nav1.2 and Nav1.6‐encoded sodium channels. Molecular and Cellular Neuroscience 42 (2): 90–101.

Lampert A, Eberhardt M and Waxman SG (2014) Altered sodium channel gating as molecular basis for pain: contribution of activation, inactivation, and resurgent currents. Handbook of Experimental Pharmacology 221: 91–110.

Leipold E, Liebmann L, Korenke GC, et al. (2013) A de novo gain‐of‐function mutation in SCN11A causes loss of pain perception. Nature Genetics 45 (11): 1399–1404.

Nau C, Wang SY, Strichartz GR and Wang GK (1999) Point mutations at N434 in D1‐S6 of mu1 Na(+) channels modulate binding affinity and stereoselectivity of local anesthetic enantiomers. Molecular Pharmacology 56 (2): 404–413.

Noda M, Suzuki H, Numa S and Stuhmer W (1989) A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II. FEBS Letters 259 (1): 213–216.

O'Reilly AO, Eberhardt E, Weidner C, et al. (2012) Bisphenol a binds to the local anesthetic receptor site to block the human cardiac sodium channel. PLoS One 7 (7): e41667.

Ong BH, Tomaselli GF and Balser JR (2000) A structural rearrangement in the sodium channel pore linked to slow inactivation and use dependence. Journal of General Physiology 116 (5): 653–662.

Payandeh J, Scheuer T, Zheng N and Catterall WA (2011) The crystal structure of a voltage‐gated sodium channel. Nature 475 (7356): 353–358.

Raman IM and Bean BP (1997) Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. Journal of Neuroscience 17 (12): 4517–4526.

Stuhmer W, Conti F, Suzuki H, et al. (1989) Structural parts involved in activation and inactivation of the sodium channel. Nature 339 (6226): 597–603.

Theile JW, Jarecki BW, Piekarz AD and Cummins TR (2011) Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navbeta4 peptide‐mediated resurgent sodium currents. Journal of Physiology 589 (Pt 3): 597–608.

Van Petegem F, Lobo PA and Ahern CA (2012) Seeing the forest through the trees: towards a unified view on physiological calcium regulation of voltage‐gated sodium channels. Biophysical Journal 103 (11): 2243–2251.

Veeramah KR, O'Brien JE, Meisler MH, et al. (2012) De novo pathogenic SCN8A mutation identified by whole‐genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. American Journal of Human Genetics 90 (3): 502–510.

Vilin YY, Makita N, George AL Jr and Ruben PC (1999) Structural determinants of slow inactivation in human cardiac and skeletal muscle sodium channels. Biophysical Journal 77 (3): 1384–1393.

Wang SY and Wang GK (1997) A mutation in segment I‐S6 alters slow inactivation of sodium channels. Biophysical Journal 72 (4): 1633–1640.

Weiss J, Pyrski M, Jacobi E, et al. (2011) Loss‐of‐function mutations in sodium channel Nav1.7 cause anosmia. Nature 472 (7342): 186–190.

Zhang, X. Y., J. Wen, W. Yang, C. Wang, L. Gao, L. H. Zheng, T. Wang, K. Ran, Y. Li, X. Li, M. Xu, J. Luo, S. Feng, X. Ma, H. Ma, Z. Chai, Z. Zhou, J. Yao, X. Zhang and J. Y. Liu (2013). Am Gain‐of‐function mutations in SCN11A cause familial episodic pain Journal of Human Genetics. 93(5): 957–966.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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