NaV1.4 channels

Channel name NaV1.4
Description Voltage-gated sodium channel α subunit
Other names SkM1, μ11
Molecular information Human: 1836aa, M81758, O60217, Q9H3L9,2,3 chr. 17q23-25,3 SCN4A
Rat: 1840aa, M26643, O706111
Mouse: 1841aa, AJ278787, Q9ER60,4 chr. 11[64],5 Scn4A
Associated subunits β1
Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
Current INa
Conductance 24.9pS human6
19.8pS rat7
Ion selectivity Na+ > K+ > Rb+ > Cs (channels reconstituted from rat skeletal muscle sarcolemma)8
Activation Va = —30 mV (rat α subunit in Xenopus oocytes)9
Va = —26 mV (human α subunit in CHO cells)10
Inactivation Vh = —50.1 mV, τh = 0.8 and ∼8 ms at —30 mV, τh = ∼0.3 and ∼3.5 ms at 10 mV (human α subunit in Xenopus oocytes with 200-ms depolarizations using macropatch voltage-clamp)6
Vh = —56 mV, τh = 1.1 ms at —20 mV (human α subunit in CHO cells with 500-ms depolarizations)10
Activators Protein: β-scorpion toxins11
Alkaloids: veratridine,12 batrachotoxin,12 grayanotoxin13
Gating Modifiers α-Scorpion toxins and sea anemone toxins, which all slow inactivation14
Blockers Selective: μ-conotoxin GIIIA (EC50 = 19—54 nM in rat,15,16 1.2 μM in human6), μ-conotoxin PIIIA (EC50 = 41 nM in rat16)
Nonselective: tetrodotoxin (EC50 = 5 nM in rat,1 25 nM in human6), saxitoxin (EC50 = 4.1 nM in rat17)
Drugs: local anesthetic, antiepileptic, and antiarrhythmic drugs (lidocaine EC50 = 2128 μM in resting state at — 130 mV in rat α subunit, 176 μM in rat αβ1 subunits, 4.4 μM for inactivated state in rat α subunit, 0.9 μM in rat αβ1 subunits18; mexiletine EC50 = 431 μM in resting state at —120 mV in rat αβ1 subunits, 68 μM for inactivated state in rat αβ1 subunits19)
Radioligands [125I]α scorpion toxin, [3H]batrachotoxin, [3H]saxitoxin, [3H]tetrodotoxin
Channel distribution High levels in adult skeletal muscle and low levels in neonatal skeletal muscle20
Physiological functions Action potential initiation and transmission in skeletal muscle
Mutations and pathophysiology Point mutations in many locations cause hyperkalemic periodic paralysis, paramyotonia congenita, potassium-aggravated myotonias21
Pharmacological significance Target of local anesthetics used to treat myotonia
  • aa, amino acids; chr., chromosome; CHO, Chinese hamster ovary.

  • 1. Trimmer JS, Cooperman SS, Tomiko SA, Zhou J, Crean SM, Boyle MB, Kallen RG, Sheng Z, Barchi RL, Sigworth FJ, et al. (1989) Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuron 3:33-49

  • 2. George AL Jr, Komisarof J, Kallen RG, and Barchi RL (1992) Primary structure of the adult human skeletal muscle voltage-dependent sodium channel. Ann Neurol 31:131-137

  • 3. Wang J, Rojas CV, Zhou J, Schwartz LS, Nicholas H, and Hoffman EP (1992) Sequence and genomic structure of the human adult skeletal muscle sodium channel alpha subunit gene on 17q. Biochem Biophys Res Commun 182:794-801

  • 4. Zimmer T, Bollensdorff C, Haufe V, Birch-Hirschfeld E, and Benndorf K (2002) Mouse heart Na+ channels: primary structure and function of two isoforms and alternatively splice variants. Am J Physiol Heart Circ Physiol 282:H1007-H1017

  • 5. Ambrose C, Cheng S, Fontaine B, Nadeau JH, MacDonald M, and Gusella JF (1992) The alpha-subunit of the skeletal muscle sodium channel is encoded proximal to Tk-1 on mouse chromosome 11. Mamm Genome 3:151-155

  • 6. Chahine M, Bennett PB, George AL Jr, and Horn R (1994) Functional expression and properties of the human skeletal muscle sodium channel. Pflugers Arch Eur J Physiol 427:136-142

  • 7. Zhou J, Potts JF, Trimmer JS, Agnew WS, and Sigworth FJ (1991) Multiple gating modes and the effect of modulating factors on the muI sodium channel. Neuron 7:775-785

  • 8. Tanaka JC, Eccleston JF, and Barchi RL (1983) Cation selectivity characteristics of the reconstituted voltage-dependent sodium channel purified from rat skeletal muscle sarcolemma. J Biol Chem 258:7519-7526

  • 9. Cannon SC, McClatchey AI, and Gusella JF (1993) Modification of the Na+ current conducted by the rat skeletal muscle alpha subunit by co-expression with a human brain beta subunit. Pflugers Arch Eur J Physiol 423:155-157

  • 10. Bennett ES (2004) Channel activation voltage alone is directly altered in an isoform-specific manner by Nav1.4 and Nav1.5 cytosplasmic linkers. J Membr Biol 197:155-168

  • 11. Marcotte P, Chen L-Q, Kallen RG, and Chahine M (1997) Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels. Circ Res 80:363-369

  • 12. Wang S-Y and Wang GK (1998) Point mutations in segment I-S6 render voltage-gated Na+ channels resistant to batrachotoxin. Proc Natl Acad Sci USA 95:2653-2658

  • 13. Kimura T, Yamaoka K, Kinoshita E, Maejima H, Yuki T, Yakehiro M, and Seyama I (2001) Novel site on sodium channel α-subunit responsible for the differential sensitivity of grayanotoxin in skeletal and cardiac muscle. Mol Pharmacol 60:865-872

  • 14. Chahine M, Plante E, and Kallen RG (1996) Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel α-subunits expressed in tsA201 cells. J Membr Biol 152:39-48

  • 15. Chen L-Q, Chahine M, Kallen RG, and Horn R (1992) Chimeric study of sodium channels from rat skeletal and cardiac muscle. FEBS Lett 309:253-257

  • 16. Safo P, Rosenbaum T, Shcherbatko A, Choi D-Y, Han E, Toledo-Aral J, Olivera BM, Brehm P, and Mandel G (2000) Distinction among neuronal subtypes of voltage-activated sodium channels by μ-conotoxin PIIIA. J Neurosci 20:76-80

  • 17. Penzotti JL, Lipkind G, Fozzard HA, and Dudley SC Jr (2001) Specific neosaxitoxin interactions with the Na+ channel outer vestibule determined by mutant cycle analysis. Biophys J 80:698-706

  • 18. Makielski JC, Limberis J, Fan Z and Kyle JW (1999) Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes dependes on α (hH1 vs. rSkM1) and β1 subunits. Cardiovasc Res 42:503-509

  • 19. Wang GK, Russell C, and Wang S-Y (2004) Mexiletine block of wild-type and inactivation-deficient human skeletal muscle hNav1.4 Na+ channels. J Physiol (Lond) 554:621-633

  • 20. Trimmer JS, Cooperman SS, Agnew WS, and Mandel G (1990) Regulation of muscle sodium channel transcripts during development and in response to denervation. Dev Biol 142:360-367

  • 21. Cannon SC (1997) From mutation to myotonia in sodium channel disorders. Neuromuscul Disord 7:241-249