Sodium (voltage-gated)

Overview: 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 (Isom, 2001). 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. 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) and approved by the NC-IUPHAR subcommittee on sodium channels (Catterall et al., 2005).

Nomenclature	NaV1.1	NaV1.2	NaV1.3	NaV1.4	NaV1.5
Alternative names	Brain type I	Brain type II	Brain type III	µ1, SkM1	h1, SkM II, cardiac
Ensembl ID	ENSG00000144285	ENSG00000136531	ENSG00000153253	ENSG00000007314	ENSG00000183873
Activators	Veratridine, batrachotoxin	Veratridine, batrachotoxin	Veratridine, batrachotoxin	Veratridine, batrachotoxin	Veratridine, batrachotoxin
Blockers	Tetrodotoxin (10 nM), saxitoxin	Tetrodotoxin (10 nM), saxitoxin	Tetrodotoxin (2–15 nM), saxitoxin	µ-Conotoxin GIIIA, tetrodotoxin (5 nM), saxitoxin	Tetrodotoxin (2 µM)
Functional characteristic	Fast inactivation (0.7 ms)	Fast inactivation (0.8 ms)	Fast inactivation (0.8 ms)	Fast inactivation (0.6 ms)	Fast inactivation (1 ms)

Nomenclature	NaV1.6	NaV1.7	NaV1.8	NaV1.9
Alternative names	PN4, NaCH6	PN1, NaS	SNS, PN3	NaN, SNS2
Ensembl ID	ENSG00000196876	ENSG00000169432	ENSG00000185313	ENSG00000168356
Activators	Veratridine, batrachotoxin	Veratridine, batrachotoxin	–	–
Blockers	Tetrodotoxin (6 nM), saxitoxin	Tetrodotoxin (4 nM), saxitoxin	Tetrodotoxin (60 µM)	Tetrodotoxin (40 µM)
Functional characteristic	Fast inactivation (1 ms)	Fast inactivation (0.5 ms)	Slow inactivation (6 ms)	Slow inactivation (16 ms)

Sodium channels are also blocked by local anaesthetic agents, anti-arrythmic drugs and antiepileptic drugs. There are two clear functional fingerprints for distinguishing different subtypes. These are sensitivity to tetrodotoxin (Na_V1.5, Na_V1.8 and Na_V1.9 are much less sensitive to block) and rate of inactivation (Na_V1.8 and particularly Na_V1.9 inactivate more slowly).

Further Reading

Baker MD, Wood JN (2001). Involvement of Na⁺ channels in pain pathways. Trends Pharmacol Sci22: 27–31.

Bean BP (2007). The action potential in mammalian central neurons. Nat Rev Neurosci8: 451–465.

Cantrell AR, Catterall WA (2001). Neuromodulation of Na⁺ channels: an unexpected form of cellular plasticity. Nat Rev Neurosci2: 397–407.

Catterall WA (1995). Structure and function of voltage-gated ion channels. Ann Rev Biochem64: 493–531.

Catterall WA (2000). From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron26: 13–25.

Catterall WA, Goldin AL, Waxman SG (2005). International Union of Pharmacology. XLVII. Nomenclature and structure function relationships of voltage-gated sodium channels. Pharmacol Rev57: 397–409.

Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D (2008). Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci28: 11768–11777.

Fozzard HA, Hanck DA (1996). Structure and function of voltage-dependent sodium channels – comparison of brain-II and cardiac isoforms. Physiol Rev76: 887–926.

Fozzard HA, Lee PJ, Lipkind GM (2005). Mechanism of local anesthetic drug action on voltage-gated sodium channels. Curr Pharm Des11: 2671–2686.

George AL (2005). Inherited disorders of voltage-gated sodium channels. J Clin Invest115: 1990–1999.

Goldin AL (2001). Resurgence of sodium channel research. Ann Rev Physiol63: 874–894.

Han TS, Teichert RW, Olivera BM, Bulaj G (2008). Conus venoms – a rich source of peptide-based therapeutics. Curr Pharm Des14: 2462–2479.

Isom LL (2001). Sodium channel beta subunits: anything but auxiliary. Neuroscientist7: 42–54.

Kyle DJ, Ilyin VI (2007). Sodium channel blockers. J Med Chem50: 2583–2588.

Lai J, Porreca F, Hunter JC, Gold MS (2004). Voltage-gated sodium channels and hyperalgesia. Ann Rev Pharmacol Toxicol44: 371–397.

Lewis RJ, Garcia ML (2003). Therapeutic potential of venom peptides. Nat Rev Drug Discov2: 790–802.

Matulenko MA, Scanio MJ, Kort ME (2009). Voltage-gated sodium channel blockers for the treatment of chronic pain. Curr Top Med Chem 9: 362–376.

Priest BT, Kaczorowski GJ (2007). Blocking sodium channels to treat neuropathic pain. Expert Opin Ther Targets11: 291–306.

Priestley T (2004). Voltage-gated sodium channels and pain. Curr Drug Targets CNS Neurol Disord3: 441–456.

Terlau H, Olivera BM (2004). Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev84: 41–68.

Trimmer JS, Rhodes KJ (2004). Localisation of voltage-gated ion channels in mammalian brain. Ann Rev Physiol66: 477–519.

Wood JN, Boorman J (2005). Voltage-gated sodium channel blockers; target validation and therapeutic potential. Curr Top Med Chem5: 529–537.

Yu FH, Catterall WA (2004). The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis. Sci STKE2004 (253): re15.