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- Voltage-gated sodium channels (NaV)
Voltage-gated sodium channels (NaV) C
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).
Overview
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Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise one pore-forming α subunit, which may be associated with either one or two β subunits [23]. 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 [34]. 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 [34]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain. Pharmacological targeting of voltage-gated sodium channels has long been a cornerstone of clinical treatment for a range of conditions. Classical sodium channel blockers, many of which act by occluding the central pore, are widely used as local anesthetics, antiarrhythmic agents, and anticonvulsants [12]. More recently, suzetrigine, a highly selective Nav1.8 inhibitor, received FDA approval for the treatment of acute post-operative pain [27,43].
The nomenclature for sodium channels was proposed by Goldin et al., (2000) [20] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [5]).
Channels and Subunits
Targets of relevance to immunopharmacology are highlighted in blue
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Nav1.1 C
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Nav1.2 C
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Nav1.3 C
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Nav1.4 C
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Nav1.5
C
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Nav1.6 C
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Nav1.7 C
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Nav1.8 C
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Nav1.9 C
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Further reading
* Key recommended reading is highlighted with an asterisk
* Alsaloum M, Dib-Hajj SD, Page DA, Ruben PC, Krainer AR, Waxman SG. (2025) Voltage-gated sodium channels in excitable cells as drug targets. Nat Rev Drug Discov, 24 (5): 358-378. [PMID:39901031]
Andavan GS, Lemmens-Gruber R. (2011) Voltage-gated sodium channels: mutations, channelopathies and targets. Curr Med Chem, 18 (3): 377-97. [PMID:21143119]
Baker MD, Wood JN. (2001) Involvement of Na+ channels in pain pathways. Trends Pharmacol Sci, 22 (1): 27-31. [PMID:11165669]
Bean BP. (2007) The action potential in mammalian central neurons. Nat Rev Neurosci, 8 (6): 451-65. [PMID:17514198]
Cantrell AR, Catterall WA. (2001) Neuromodulation of Na+ channels: an unexpected form of cellular plasticity. Nat Rev Neurosci, 2 (6): 397-407. [PMID:11389473]
Catterall WA. (1995) Structure and function of voltage-gated ion channels. Annu Rev Biochem, 64: 493-531. [PMID:7574491]
Catterall WA. (2000) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron, 26 (1): 13-25. [PMID:10798388]
Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D. (2008) Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci, 28 (46): 11768-77. [PMID:19005038]
* 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]
* Catterall WA, Wisedchaisri G, Zheng N. (2017) The chemical basis for electrical signaling. Nat Chem Biol, 13 (5): 455-463. [PMID:28406893]
* Deuis JR, Mueller A, Israel MR, Vetter I. (2017) The pharmacology of voltage-gated sodium channel activators. Neuropharmacology, 127: 87-108. [PMID:28416444]
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. (2010) Sodium channels in normal and pathological pain. Annu Rev Neurosci, 33: 325-47. [PMID:20367448]
England S, de Groot MJ. (2009) Subtype-selective targeting of voltage-gated sodium channels. Br J Pharmacol, 158 (6): 1413-25. [PMID:19845672]
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]
George AL. (2005) Inherited disorders of voltage-gated sodium channels. J Clin Invest, 115 (8): 1990-9. [PMID:16075039]
* Ghovanloo MR, Ruben PC. (2022) Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications. Neuroscientist, 28 (4): 318-334. [PMID:34027742]
Goldin AL. (2001) Resurgence of sodium channel research. Annu Rev Physiol, 63: 871-94. [PMID:11181979]
Han TS, Teichert RW, Olivera BM, Bulaj G. (2008) Conus venoms - a rich source of peptide-based therapeutics. Curr Pharm Des, 14 (24): 2462-79. [PMID:18781995]
Isom LL. (2001) Sodium channel beta subunits: anything but auxiliary. Neuroscientist, 7 (1): 42-54. [PMID:11486343]
* Jiang D, Gamal El-Din TM, Ing C, Lu P, Pomès R, Zheng N, Catterall WA. (2018) Structural basis for gating pore current in periodic paralysis. Nature, 557 (7706): 590-594. [PMID:29769724]
* Kanellopoulos AH, Matsuyama A. (2016) Voltage-gated sodium channels and pain-related disorders. Clin Sci, 130 (24): 2257-2265. [PMID:27815510]
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]
Lewis RJ, Garcia ML. (2003) Therapeutic potential of venom peptides. Nat Rev Drug Discov, 2 (10): 790-802. [PMID:14526382]
Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. (2010) Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol, 9 (4): 413-24. [PMID:20298965]
Matulenko MA, Scanio MJ, Kort ME. (2009) Voltage-gated sodium channel blockers for the treatment of chronic pain. Curr Top Med Chem, 9 (4): 362-76. [PMID:19442207]
Priest BT, Kaczorowski GJ. (2007) Blocking sodium channels to treat neuropathic pain. Expert Opin Ther Targets, 11 (3): 291-306. [PMID:17298289]
Priestley T. (2004) Voltage-gated sodium channels and pain. Curr Drug Targets CNS Neurol Disord, 3 (6): 441-56. [PMID:15578963]
* Shen H, Li Z, Jiang Y, Pan X, Wu J, Cristofori-Armstrong B, Smith JJ, Chin YKY, Lei J, Zhou Q et al.. (2018) Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science, 362 (6412). [PMID:30049784]
Terlau H, Olivera BM. (2004) Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev, 84 (1): 41-68. [PMID:14715910]
* Terragni B, Scalmani P, Franceschetti S, Cestèle S, Mantegazza M. (2018) Post-translational dysfunctions in channelopathies of the nervous system. Neuropharmacology, 132: 31-42. [PMID:28571716]
Trimmer JS, Rhodes KJ. (2004) Localization of voltage-gated ion channels in mammalian brain. Annu Rev Physiol, 66: 477-519. [PMID:14977411]
* Waxman SG. (2023) Targeting a Peripheral Sodium Channel to Treat Pain. N Engl J Med, 389 (5): 466-469. [PMID:37530829]
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]
Yu FH, Catterall WA. (2004) The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE, 2004 (253): re15. [PMID:15467096]
References
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5. 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]
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13. Ghovanloo MR, Choudhury K, Bandaru TS, Fouda MA, Rayani K, Rusinova R, Phaterpekar T, Nelkenbrecher K, Watkins AR, Poburko D et al.. (2021) Cannabidiol inhibits the skeletal muscle Nav1.4 by blocking its pore and by altering membrane elasticity. J Gen Physiol, 153 (5). [PMID:33836525]
14. Ghovanloo MR, Effraim PR, Tyagi S, Zhao P, Dib-Hajj SD, Waxman SG. (2024) Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol. Commun Biol, 7 (1): 120. [PMID:38263462]
15. Ghovanloo MR, Estacion M, Higerd-Rusli GP, Zhao P, Dib-Hajj S, Waxman SG. (2022) Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability. Br J Pharmacol, 179 (15): 4010-4030. [PMID:35297036]
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20. Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, Kallen RG, Mandel G, Meisler MH, Netter YB et al.. (2000) Nomenclature of voltage-gated sodium channels. Neuron, 28 (2): 365-8. [PMID:11144347]
21. Goodchild SJ, Shuart NG, Williams AD, Ye W, Parrish RR, Soriano M, Thouta S, Mezeyova J, Waldbrook M, Dean R et al.. (2024) Molecular Pharmacology of Selective NaV1.6 and Dual NaV1.6/NaV1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo. ACS Chem Neurosci, 15 (6): 1169-1184. [PMID:38359277]
22. Huang J, Fan X, Jin X, Jo S, Zhang HB, Fujita A, Bean BP, Yan N. (2023) Cannabidiol inhibits Nav channels through two distinct binding sites. Nat Commun, 14 (1): 3613. [PMID:37330538]
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NC-IUPHAR subcommittee and family contributors
Subcommittee members:
William A. Catterall (Past chairperson)
Alan L. Goldin
Stephen G. Waxman |
Other contributors:
Mohammad-Reza Ghovanloo |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Striessnig J, Gibb AJ, Mathie AA, Veale EL, Kelly E, Peach CJ, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Ion channels. Br J Pharmacol. 182: S152-S241.
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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 ms) or repetitive trains of stimuli. All sodium channel subtypes are blocked by intracellular QX-314.