Groome J R, Moreau A, Delemotte L
Department of Biological Sciences, Idaho State University, Pocatello, ID, 83209, USA.
Institut NeuroMyogene, ENS de Lyon, Site MONOD, Lyon, France.
Handb Exp Pharmacol. 2018;246:371-399. doi: 10.1007/164_2017_54.
Voltage-gated sodium channels belong to the superfamily of voltage-gated cation channels. Their structure is based on domains comprising a voltage sensor domain (S1-S4 segments) and a pore domain (S5-S6 segments). Mutations in positively charged residues of the S4 segments may allow protons or cations to pass directly through the gating pore constriction of the voltage sensor domain; these anomalous currents are referred to as gating pore or omega (ω) currents. In the skeletal muscle disorder hypokalemic periodic paralysis, and in arrhythmic dilated cardiomyopathy, inherited mutations of S4 arginine residues promote omega currents that have been shown to be a contributing factor in the pathogenesis of these sodium channel disorders. Characterization of gating pore currents in these channelopathies and with artificial mutations has been possible by measuring the voltage-dependence and selectivity of these leak currents. The basis of gating pore currents and the structural basis of S4 movement through the gating pore has also been studied extensively with molecular dynamics. These simulations have provided valuable insight into the nature of S4 translocation and the physical basis for the effects of mutations that promote permeation of protons or cations through the gating pore.
电压门控钠通道属于电压门控阳离子通道超家族。其结构基于包含电压传感器结构域（S1 - S4片段）和孔道结构域（S5 - S6片段）的结构域。S4片段中带正电荷残基的突变可能使质子或阳离子直接通过电压传感器结构域的门控孔道收缩处；这些异常电流被称为门控孔道电流或ω电流。在骨骼肌疾病低钾性周期性麻痹以及心律失常性扩张型心肌病中，S4精氨酸残基的遗传性突变会促进ω电流，这些电流已被证明是这些钠通道疾病发病机制中的一个促成因素。通过测量这些泄漏电流的电压依赖性和选择性，能够对这些通道病以及人工突变情况下的门控孔道电流进行表征。门控孔道电流的基础以及S4通过门控孔道移动的结构基础也已通过分子动力学进行了广泛研究。这些模拟为S4易位的本质以及促进质子或阳离子通过门控孔道渗透的突变效应的物理基础提供了有价值的见解。
