O'Leary M E, Chahine M
Cooper Medical School of Rowan University, Camden, NJ, USA.
CERVO Brain Research Center, Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada.
Handb Exp Pharmacol. 2018;246:209-231. doi: 10.1007/164_2017_73.
Voltage-gated sodium (Na) channels are expressed in virtually all electrically excitable tissues and are essential for muscle contraction and the conduction of impulses within the peripheral and central nervous systems. Genetic disorders that disrupt the function of these channels produce an array of Na channelopathies resulting in neuronal impairment, chronic pain, neuromuscular pathologies, and cardiac arrhythmias. Because of their importance to the conduction of electrical signals, Na channels are the target of a wide variety of local anesthetic, antiarrhythmic, anticonvulsant, and antidepressant drugs. The voltage-gated family of Na channels is composed of α-subunits that encode for the voltage sensor domains and the Na-selective permeation pore. In vivo, Na channel α-subunits are associated with one or more accessory β-subunits (β-β) that regulate gating properties, trafficking, and cell-surface expression of the channels. The permeation pore of Na channels is divided in two parts: the outer mouth of the pore is the site of the ion selectivity filter, while the inner cytoplasmic pore serves as the channel activation gate. The cytoplasmic lining of the permeation pore is formed by the S6 segments that include highly conserved aromatic amino acids important for drug binding. These residues are believed to undergo voltage-dependent conformational changes that alter drug binding as the channels cycle through the closed, open, and inactivated states. The purpose of this chapter is to broadly review the mechanisms of Na channel gating and the models used to describe drug binding and Na channel inhibition.
电压门控钠（Na）通道几乎在所有电可兴奋组织中均有表达，对于肌肉收缩以及外周和中枢神经系统内的冲动传导至关重要。破坏这些通道功能的遗传疾病会产生一系列钠通道病，导致神经元损伤、慢性疼痛、神经肌肉疾病和心律失常。由于其对电信号传导的重要性，钠通道是多种局部麻醉药、抗心律失常药、抗惊厥药和抗抑郁药的作用靶点。电压门控钠通道家族由编码电压传感器结构域和钠选择性渗透孔的α亚基组成。在体内，钠通道α亚基与一个或多个辅助β亚基（β-β）相关联，这些β亚基调节通道的门控特性、转运和细胞表面表达。钠通道的渗透孔分为两部分：孔的外口是离子选择性过滤器的位置，而内部细胞质孔则作为通道激活门。渗透孔的细胞质内衬由S6片段形成，这些片段包含对药物结合很重要的高度保守的芳香族氨基酸。据信这些残基会经历电压依赖性构象变化，随着通道在关闭、开放和失活状态之间循环，这种变化会改变药物结合。本章的目的是广泛综述钠通道门控机制以及用于描述药物结合和钠通道抑制的模型。
