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