Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
J Physiol. 2012 Jun 1;590(11):2577-89. doi: 10.1113/jphysiol.2011.224204. Epub 2012 Apr 2.
Voltage-gated sodium channels initiate action potentials in nerve, muscle and other excitable cells. The sodium current that initiates the nerve action potential was discovered by Hodgkin and Huxley using the voltage clamp technique in their landmark series of papers in The Journal of Physiology in 1952. They described sodium selectivity, voltage-dependent activation and fast inactivation, and they developed a quantitative model for action potential generation that has endured for many decades. This article gives an overview of the legacy that has evolved from their work, including development of conceptual models of sodium channel function, discovery of the sodium channel protein, analysis of its structure and function, determination of its structure at high resolution, definition of the mechanism and structural basis for drug block, and exploration of the role of the sodium channel as a target for disease mutations. Structural models for sodium selectivity and conductance, voltage-dependent activation, fast inactivation and drug block are discussed. A perspective for the future envisions new advances in understanding the structural basis for sodium channel function, the role of sodium channels in disease and the opportunity for discovery of novel therapeutics.
电压门控钠离子通道在神经、肌肉和其他可兴奋细胞中引发动作电位。霍奇金和赫胥黎于 1952 年在《生理学杂志》上发表了一系列里程碑式的论文，使用电压钳技术发现了引发神经动作电位的钠离子电流。他们描述了钠离子的选择性、电压依赖性激活和快速失活，并为动作电位的产生建立了一个持续了几十年的定量模型。本文概述了从他们的工作中发展而来的遗产，包括钠离子通道功能的概念模型的发展、钠离子通道蛋白的发现、对其结构和功能的分析、在高分辨率下确定其结构、确定药物阻断的机制和结构基础，以及探索钠离子通道作为疾病突变靶点的作用。讨论了钠离子选择性和电导、电压依赖性激活、快速失活和药物阻断的结构模型。对未来的展望设想了在理解钠离子通道功能的结构基础、钠离子通道在疾病中的作用以及发现新型治疗方法方面的新进展。
