Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

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.

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…Splicing of U11/U12 introns is less efficient than splicing of standard introns, which is thought to be a rate-limiting factor in the expression of genes that contain a U11/U12 intron (Turunen et al 2013). Interestingly, a rare class of genes with more than one U11/U12 intron is the voltage-gated ion channel superfamily of genes (Wu and Krainer 1999), which themselves are mutated in neurodegenerative and neuromuscular disease (Andavan and Lemmens-Gruber 2011), suggesting that selectively compromised splicing of these transcripts may have disease relevance. Recently, it was shown in mice that SMN deficiency leads to intron retention, particularly among U11/ U12 introns, which can be reversed by increasing SMN levels (Jangi et al 2017).…”

Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels

“…Dysfunctions of Na v s cause a number of channelopathies (3), and approaches for treatment of these diseases are eagerly awaited.…”

Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype

“…These channelopathies include epilepsy and Dravet syndrome caused by mutations in Na v 1.1 and Na v 1.2; hyperkalemic or hypokalemic periodic paralysis syndrome caused by mutations in the skeletal muscle channel Na v 1.4; long QT syndrome, Brugada syndrome, and Sudden Infant Death syndrome caused by mutations in the cardiac channel Na v 1.5; erythromelalgia and paroxysmal extreme pain disorder caused by mutations in Na v 1.7; and altered pain sensitivity caused by mutations in Na v 1.8 and Na v 1.9 (3). These diseases underscore the importance of VGSCs in physiology, but the full spectrum of events requiring sodium channel function is not definitively known.…”