Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [12]. α-Subunits consist of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [16]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [16]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.
The nomenclature for sodium channels was proposed by Goldin et al., (2000) [11] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [4]).
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* Key recommended reading is highlighted with an asterisk
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Fozzard HA, Hanck DA. (1996) Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms. Physiol. Rev., 76 (3): 887-926. [PMID:8757791]
Fozzard HA, Lee PJ, Lipkind GM. (2005) Mechanism of local anesthetic drug action on voltage-gated sodium channels. Curr. Pharm. Des., 11 (21): 2671-86. [PMID:16101448]
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Goldin AL. (2001) Resurgence of sodium channel research. Annu. Rev. Physiol., 63: 871-94. [PMID:11181979]
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Isom LL. (2001) Sodium channel beta subunits: anything but auxiliary. Neuroscientist, 7 (1): 42-54. [PMID:11486343]
Kyle DJ, Ilyin VI. (2007) Sodium channel blockers. J. Med. Chem., 50 (11): 2583-8. [PMID:17489575]
Lai J, Porreca F, Hunter JC, Gold MS. (2004) Voltage-gated sodium channels and hyperalgesia. Annu. Rev. Pharmacol. Toxicol., 44: 371-97. [PMID:14744251]
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Priest BT, Kaczorowski GJ. (2007) Blocking sodium channels to treat neuropathic pain. Expert Opin. Ther. Targets, 11 (3): 291-306. [PMID:17298289]
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Trimmer JS, Rhodes KJ. (2004) Localization of voltage-gated ion channels in mammalian brain. Annu. Rev. Physiol., 66: 477-519. [PMID:14977411]
Wood JN, Boorman J. (2005) Voltage-gated sodium channel blockers; target validation and therapeutic potential. Curr Top Med Chem, 5 (6): 529-37. [PMID:16022675]
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1. Abdelsayed M, Sokolov S, Ruben PC. (2013) A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2. Front Pharmacol, 4: 121. [PMID:24065921]
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3. Bricelj VM, Connell L, Konoki K, Macquarrie SP, Scheuer T, Catterall WA, Trainer VL. (2005) Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP. Nature, 434 (7034): 763-7. [PMID:15815630]
4. Catterall WA, Goldin AL, Waxman SG. (2005) International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev., 57 (4): 397-409. [PMID:16382098]
5. Catterall WA, Morrow CS, Daly JW, Brown GB. (1981) Binding of batrachotoxinin A 20-alpha-benzoate to a receptor site associated with sodium channels in synaptic nerve ending particles. J. Biol. Chem., 256 (17): 8922-7. [PMID:6114956]
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9. Cummins TR, Dib-Hajj SD, Black JA, Akopian AN, Wood JN, Waxman SG. (1999) A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J. Neurosci., 19 (24): RC43. [PMID:10594087]
10. Dietrich PS, McGivern JG, Delgado SG, Koch BD, Eglen RM, Hunter JC, Sangameswaran L. (1998) Functional analysis of a voltage-gated sodium channel and its splice variant from rat dorsal root ganglia. J. Neurochem., 70 (6): 2262-72. [PMID:9603190]
11. Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, Kallen RG, Mandel G, Meisler MH, Netter YB, Noda M, Tamkun MM, Waxman SG, Wood JN, Catterall WA. (2000) Nomenclature of voltage-gated sodium channels. Neuron, 28 (2): 365-8. [PMID:11144347]
12. Isom LL. (2001) Sodium channel beta subunits: anything but auxiliary. Neuroscientist, 7 (1): 42-54. [PMID:11486343]
13. Klugbauer N, Lacinova L, Flockerzi V, Hofmann F. (1995) Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J., 14 (6): 1084-90. [PMID:7720699]
14. Linford NJ, Cantrell AR, Qu Y, Scheuer T, Catterall WA. (1998) Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel. Proc. Natl. Acad. Sci. U.S.A., 95 (23): 13947-52. [PMID:9811906]
15. Osteen JD, Herzig V, Gilchrist J, Emrick JJ, Zhang C, Wang X, Castro J, Garcia-Caraballo S, Grundy L, Rychkov GY et al.. (2016) Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature, 534 (7608): 494-9. [PMID:27281198]
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18. Penzotti JL, Lipkind G, Fozzard HA, Dudley SC. (2001) Specific neosaxitoxin interactions with the Na+ channel outer vestibule determined by mutant cycle analysis. Biophys. J., 80 (2): 698-706. [PMID:11159437]
19. Sheldon RS, Cannon NJ, Duff HJ. (1986) Binding of [3H]batrachotoxinin A benzoate to specific sites on rat cardiac sodium channels. Mol. Pharmacol., 30 (6): 617-23. [PMID:2431264]
20. Smith RD, Goldin AL. (1998) Functional analysis of the rat I sodium channel in xenopus oocytes. J. Neurosci., 18 (3): 811-20. [PMID:9437003]
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Subcommittee members:
William A. Catterall (Chairperson)
Alan L. Goldin
Stephen G. Waxman |
Database page citation:
William A. Catterall, Alan L. Goldin, Stephen G. Waxman. Voltage-gated sodium channels. Accessed on 27/04/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=82.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Striessnig J, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Voltage-gated ion channels. Br J Pharmacol. 174 Suppl 1: S160-S194.
Sodium channels are also blocked by local anaesthetic agents, antiarrythmic drugs and antiepileptic drugs. In general, these drugs are not highly selective among channel subtypes. There are two clear functional fingerprints for distinguishing different subtypes. These are sensitivity to tetrodotoxin (NaV1.5, NaV1.8 and NaV1.9 are much less sensitive to block) and rate of fast inactivation (NaV1.8 and particularly NaV1.9 inactivate more slowly). All sodium channels also have a slow inactivation process that is engaged during long depolarizations (>100 msec) or repetitive trains of stimuli. All sodium channel subtypes are blocked by intracellular QX-314.