TABLE 7

NaV1.6 channels

Channel name NaV1.6
Description Voltage-gated sodium channel α subunit
Other names NaCh6,1 PN4,2 CerIII3
Molecular information Human: 1980aa, O95788, Q9NYX2, A9UQD0, AF050736, AF225988, chr. 12q13,4 SCN8A
Rat: 1976aa, L39018, AF049239, AF0492401,2
Mouse: 1976aa, Q60858, AF050736, AF225988,5,6 chr. 15[64],5
Scn8A
Associated subunits β1, β2
Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
Current INa
Conductance Not established
Ion selectivity Na+
Activation Va = –8.8 mV (mouse α subunit in Xenopus oocytes with cut-open oocyte voltage-clamp)6
Va = –17 mV (mouse α subunit with β1 and β2 in Xenopus oocytes with cut-open oocyte voltage-clamp)6
Va = –26 mV, τa = 0.51 ms and 4.65 ms at –10 mV (mouse α subunit with inactivation removed and β1 and β2 in Xenopus oocytes with cut-open oocyte voltage-clamp)7
Va = –37.7 mV, τa not determined (rat α subunit in Xenopus oocytes with macropatch voltage-clamp)2,7
Inactivation Vh = –55 mV, τh = 1.2 and 2.1 ms at –10 mV, τh = 0.98 and 11.6 ms at 10 mV (mouse α subunit in Xenopus oocytes with 500-ms depolarizations using two-electrode voltage-clamp)6
Vh = –51 mV, τh = 7.1 ms at –20 mV, τh = 0.78 and 8.1 ms at 10 mV (mouse α subunit with β1 and β2 in Xenopus oocytes with 500-ms depolarizations using two-electrode voltage-clamp)6
Vh = –97.6 mV, τh = 1 ms at –30 mV (rat α subunit in Xenopus oocytes with 5-s depolarizations using macropatch voltage-clamp)2
Activators Veratridine, batrachotoxin (based on studies with rat brain sodium channels)
Gating modifiers α-Scorpion toxins and sea anemone toxins, which all slow inactivation8
Blockers Nonselective: tetrodotoxin (EC50 = 1 nM in rat,2 6 nM in mouse6), saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs
Radioligands [125I]α-scorpion toxin, [3H]batrachotoxin, [3H]saxitoxin
[3H]tetrodotoxin (based on studies with rat brain sodium channels)
Channel distribution Somatodendritic distribution in output neurons of the cerebellum, cerebral cortex, and hippocampus; Purkinje cells in the cerebellar granule cell layer; brainstem and spinal cord, astrocytes, and Schwann cells; DRG; nodes of Ranvier of sensory and motor axons in the PNS; nodes of Ranvier in the CNS1,9,10,11
Physiological functions Action potential initiation and transmission in central neurons and their myelinated axons; partially responsible for the resurgent and persistent current in cerebellar Purkinje cells12
Mutations and pathophysiology Point mutation in II S4-S5 causes cerebellar ataxia in jolting mice13; gene disruption causes motor endplate disease in mice5
Pharmacological significance Potential target for antiepileptic and analgesic drugs

  • aa, amino acids; chr., chromosome; DRG, dorsal root ganglion; PNS, peripheral nerve system; CNS, central nervous system.

  • ↵1. Schaller KL, Krzemien DM, Yarowsky PJ, Krueger BK, and Caldwell JH (1995) A novel, abundant sodium channel expressed in neurons and glia. J Neurosci 15:3231-3242

  • ↵2. Dietrich PS, McGivern JG, Delgado SG, Koch BD, Eglen RM, Hunter JC, and Sangameswaran L (1998) Functional analysis of a voltage-gated sodium channel and its splice variant from rat dorsal root ganglion. J Neurochem 70:2262-2272

  • ↵3. Vega-Saenz de Miera E, Rudy B, Sugimori M, and Llinas R (1997) Molecular characterization of the sodium channel subunits expressed in mammalian cerebellar Purkinje cells. Proc Natl Acad Sci USA 94:7059-7064

  • ↵4. Plummer NW, Galt J, Jones JM, Burgess DL, Sprunger LK, Kohrman DC, and Meisler MH (1998) Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A. Genomics 54:287-296

  • ↵5. Burgess DL, Kohrman DC, Galt J, Plummer NW, Jones JM, Spear B, and Meisler MH (1995) Mutation of a new sodium channel gene, Scn8a, in the mouse mutant `motor endplate disease'. Nat Genet 10:461-465

  • ↵6. Smith MR, Smith RD, Plummer NW, Meisler MH, and Goldin AL (1998) Functional analysis of the mouse Scn8a sodium channel. J Neurosci 18:6093-6102

  • ↵7. Zhou W and Goldin AL (2004) Use-dependent potentiation of the NaV1.6 sodium channel. Biophys J 87:3862-3872

  • ↵8. Oliveira JS, Redaelli E, Zaharenko AJ, Cassulini RR, Konno K, Pimenta DC, Freitas JC, Clare JJ, and Wanke E (2004) Binding specificity of sea anemone toxins to NaV 1.1–1.6 sodium channels. Unexpected contributions from differences in the IV/S3-S4 outer loop. J Biol Chem 279:33323-33335

  • ↵9. Whitaker W, Faull R, Waldvogel H, Plumpton C, Burbidge S, Emson P, and Clare J (1999) Localization of the type VI voltage-gated sodium channel protein in human CNS. Neuroreport 10:3703-3709

  • ↵10. Tzoumaka E, Tischler AC, Sangameswaran L, Eglen RM, Hunter JC, and Novakovic SD (2000) Differential distribution of the tetrodotoxin-sensitive rPN4/NaCh6/Scn8a sodium channel in the nervous system. J Neurosci Res 60:37-44

  • ↵11. Caldwell JH, Schaller KL, Lasher RS, Peles E, and Levinson SR (2000) Sodium channel NaV1.6 is localized at nodes of Ranvier, dendrites, and synapses. Proc Natl Acad Sci USA 97:5616-5620

  • ↵12. Raman IM, Sprunger LK, Meisler MH, and Bean BP (1997) Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice. Neuron 19:881-891

  • ↵13. Kohrman DC, Smith MR, Goldin AL, Harris J, and Meisler MH (1996) A missense mutation in the sodium channel Scn8a is responsible for cerebellar ataxia in the mouse mutant jolting. J Neurosci 16:5993-5999