NaV1.5 channels

Channel name NaV1.5
Description Voltage-gated sodium channel α subunit
Other names h1, skm II, cardiac sodium channel
Molecular information Human: 2016aa, Q14524, M77235, NM_198056 chr. 2q24, SCN5a
Rat: 1951aa, P15389, A33996, NM_013125
Mouse: 2019aa, Q9JJV9, AJ271477, NP067510, chr. 2
Associated subunits β1, β2, β3, β4
Functional assays Voltage-clamp, neurotoxin-activated ion flux, voltage-sensitive dyes
Current INa
Conductance 19–22pS1
Ion selectivity Na+ > K+ > Ca2+
Activation Va = –47 mV, –56 mV with F as the major anion in the intracellular solution2,3
Va = –27 mV with aspartate as the major anion in the intracellular solution4
τa = 2.8 ms, 1.6 ms at Va2,4
Inactivation Vh = –84 mV, –100 mV with F as the major anion in the intracellular solution2,3
Vh = –61 mV with aspartate as the major anion in the intracellular solution, τh = 1 ms at 0 mV4
Activators Veratridine, batrachotoxin, aconitine, and related natural organic toxins
Gating modifiers β-Scorpion toxins, sea anemone toxins, and δ-conotoxins, which all slow inactivation (see “Comments”)
Blockers Tetrodotoxin (TTX-insensitive, Kd = 1–2 mM),5 saxitoxin; local anesthetic, antiepileptic, and antiarrhythmic drugs (EC50 = 16 mM for lidocaine block of inactivated channels6)
Radioligands [3H]batrachotoxin (Kd = 25 nM in the presence of α-scorpion toxin)7,8
Channel distribution Cardiac myocytes,9 immature and denervated skeletal muscle,10 certain brain neurons11
Physiological functions Action potential initiation and conduction
Mutations and pathophysiology Point mutations and deletions cause long QT syndrome and idiopathic ventricular fibrillation due to slow and incomplete inactivation of the cardiac sodium current and resulting prolongation of the action potential12
Pharmacological significance Site of action of antiarrhythmic drugs; site of toxic side effects of local anesthetics that reach the general circulation
Comments NaV1.5 has lower affinity for α- and β-scorpion toxins than neuronal sodium channels13
  • aa, amino acids; chr., chromosome; TTX, tetrodotoxin.

  • 1. Fozzard HA and Hanck, DA (1996) Structure and function of voltage-dependent sodium channels: Comparison of brain II and cardiac isoforms. Physiol Rev 76:887-926

  • 2. Sheets MF and Hanck DA (1999) Gating of skeletal and cardiac muscle sodium channels in mammalian cells. J Physiol 514:425-436

  • 3. Li RA, Ennis IL, Tomaselli GF, and Marban E (2002) Structural basis of differences in isoform-specific gating and lidocaine block between cardiac and skeletal muscle sodium channels. Mol Pharmacol 61:136-141

  • 4. Mantegazza M, Yu FH, Catterall WA, and Scheuer T (2001) Role of the C-terminal domain in inactivation of brain and cardiac sodium channels. Proc Natl Acad Sci USA 98:15348-15353

  • 5. Satin J, Kyle JW, Chen M, Bell P, Cribbs LL, Fozzard HA, and Rogart RB (1992) A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties Science 256:1202-1205

  • 6. Nuss HB, Tomaselli GF, and Marbán E (1995) Cardiac sodium channels (hH1) are intrinsically more sensitive to block by lidocaine than are skeletal muscle (μ1) channels. J Gen Physiol 106:1193-1209

  • 7. Sheldon RS, Cannon NJ, and Duff HJ (1986) Binding of [3H]batrachotoxinin A benzoate to specific sites on rat cardiac sodium channels. Mol Pharmacol 30:617-623

  • 8. Taouis M, Sheldon RS, Hill RJ, and Duff HJ (1991) Cyclic AMP-dependent regulation of the number of [3H]batrachotoxinin benzoate binding sites on rat cardiac myocytes. J Biol Chem 266:10300-10304

  • 9. Rogart RB, Cribbs LL, Muglia LK, Kephart DD, and Kaiser MW (1989) Molecular cloning of a putative tetrodotoxin-resistant rat heart Na+ channel isoform. Proc Natl Acad Sci USA 86:8170-8174

  • 10. Kallen RG, Sheng ZH, Yang J, Chen LQ, Rogart RB, and Barchi RL (1990) Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle. Neuron 4:233-242

  • 11. Hartmann HA, Colom LV, Sutherland ML, and Noebels JL (1999) Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nat Neurosci 2:593-595

  • 12. Keating MT and Sanguinetti MC (2001) Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569-580

  • 13. Rogers JC, Qu Y, Tanada TN, Scheuer T, and Catterall WA (1996) Molecular determinants of high affinity binding of α-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel α subunit. J Biol Chem 271:15950-15962