Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

G.      S.B. Andavan; R.      Lemmens-Gruber

Abstract

Voltage-gated sodium channels produce fast depolarization, which is responsible for the rising phase of the action potential in neurons, muscles and heart. These channels are very large membrane proteins and are encoded by ten genes in mammals. Sodium channels are a crucial component of excitable tissues; hence, they are a target for various neurotoxins that are produced by plants and animals for defence and protection, such as tetrodotoxin, scorpion toxins and batrachotoxin. Several mutations in various sodium channel subtypes cause multiple inherited diseases known as channelopathies. When these mutated sodium channel subtypes are expressed in various tissues, channelopathies in brain, skeletal muscle and cardiac muscle develop as well as neuropathic pain. In this review, we discuss aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels. In addition, we report novel mutations that underlie a spectrum of diseases, such as Brugada, long QT syndrome and inherited conduction disorders. Furthermore, this review explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of the channel subtypes.

Keywords: Voltage-gated sodium channel, channelopathy, sodium channel mutations, sodium channel subtypes, subtype selective sodium channel blockers, subtype selective sodium channel toxins, complex multimeric structure, modifying -subunits, channel trafficking, cell adhesion, stability of the membrane, gating modulation, ion selectivity, two hydrophobic, depolarization, ganglion, chromosome, micromolar, aromatic tyrosine, phenylalanine, Coding exons, cardiac cells [41-4, skeletal muscle, CHANNELOPATHIES, hypoexcitability, Epilepsy Associated, febrile seizure, neonatal-infantile seizure, antiepileptic drugs, paralysis, potassium-aggravated myotonia, myotonia fluctuans, paramyotonia congenita, hypokalemic periodic paralysis, myotonia, arrhythmic syndromes, sinus node dysfunction, atrial fibrillation, celectrocardiogram, ventricular tachycardia, tachyarrhythmia, cardiac death, fibrillation, Infant, ventricular myocar-dium, Sick Sinus Syndrome, sinoatrial, atrial standstill, pacemaker, tachycardia-bradycardia syndrome, hyperpolarization-activated, microglial cells, Neuropathic Pain, phosphorylation, density, hreshold channel, pain, trigeminal ganglia, Drosophila, insecticide pyrethroids, mammalian isoforms, Toxins, polar, Scorpion Toxins, scorpion venom, glutamic acid, heterologous expression system, channel-selective blocker