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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 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]).
Channels and Subunits
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Nav1.1
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Nav1.2
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Nav1.3
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Nav1.4
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Nav1.5
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Nav1.6
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Nav1.7
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Nav1.8
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Nav1.9
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Further reading
* Key recommended reading is highlighted with an asterisk
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]
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]
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
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]
2. Akopian AN, Sivilotti L, Wood JN. (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 379 (6562): 257-62. [PMID:8538791]
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]
6. Chahine M, Bennett PB, George Jr AL, Horn R. (1994) Functional expression and properties of the human skeletal muscle sodium channel. Pflugers Arch, 427 (1-2): 136-42. [PMID:8058462]
7. Chen YH, Dale TJ, Romanos MA, Whitaker WR, Xie XM, Clare JJ. (2000) Cloning, distribution and functional analysis of the type III sodium channel from human brain. Eur J Neurosci, 12 (12): 4281-9. [PMID:11122339]
8. Cribbs LL, Satin J, Fozzard HA, Rogart RB. (1990) Functional expression of the rat heart I Na+ channel isoform. Demonstration of properties characteristic of native cardiac Na+ channels. FEBS Lett, 275 (1-2): 195-200. [PMID:2175715]
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 et al.. (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 USA, 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]
16. Payandeh J, Scheuer T, Zheng N, Catterall WA. (2011) The crystal structure of a voltage-gated sodium channel. Nature, 475 (7356): 353-8. [PMID:21743477]
17. Payne CE, Brown AR, Theile JW, Loucif AJ, Alexandrou AJ, Fuller MD, Mahoney JH, Antonio BM, Gerlach AC, Printzenhoff DM et al.. (2015) A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Br J Pharmacol, 172 (10): 2654-70. [PMID:25625641]
18. Penzotti JL, Lipkind G, Fozzard HA, Dudley Jr 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]
21. Walker JR, Novick PA, Parsons WH, McGregor M, Zablocki J, Pande VS, Du Bois J. (2012) Marked difference in saxitoxin and tetrodotoxin affinity for the human nociceptive voltage-gated sodium channel (Nav1.7) [corrected]. Proc Natl Acad Sci USA, 109 (44): 18102-7. [PMID:23077250]
22. Wang G, Dugas M, Armah BI, Honerjäger P. (1990) Sodium channel comodification with full activator reveals veratridine reaction dynamics. Mol Pharmacol, 37 (2): 144-8. [PMID:2154667]
23. Wang SY, Wang GK. (1998) Point mutations in segment I-S6 render voltage-gated Na+ channels resistant to batrachotoxin. Proc Natl Acad Sci USA, 95 (5): 2653-8. [PMID:9482942]
24. Zeng D, Kyle JW, Martin RL, Ambler KS, Hanck DA. (1996) Cardiac sodium channels expressed in a peripheral neurotumor-derived cell line, RT4-B8. Am J Physiol, 270 (5 Pt 1): C1522-31. [PMID:8967455]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
William A. Catterall (Chairperson)
Alan L. Goldin
Stephen G. Waxman |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.
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.