Department of Pharmacology, University of Washington, Seattle, WA, USA.
Channels (Austin). 2023 Dec;17(1):2281714. doi: 10.1080/19336950.2023.2281714. Epub 2023 Nov 20.
Voltage-gated sodium channels initiate action potentials in nerve and muscle, and voltage-gated calcium channels couple depolarization of the plasma membrane to intracellular events such as secretion, contraction, synaptic transmission, and gene expression. In this Review and Perspective article, I summarize early work that led to identification, purification, functional reconstitution, and determination of the amino acid sequence of the protein subunits of sodium and calcium channels and showed that their pore-forming subunits are closely related. Decades of study by antibody mapping, site-directed mutagenesis, and electrophysiological recording led to detailed two-dimensional structure-function maps of the amino acid residues involved in voltage-dependent activation and inactivation, ion permeation and selectivity, and pharmacological modulation. Most recently, high-resolution three-dimensional structure determination by X-ray crystallography and cryogenic electron microscopy has revealed the structural basis for sodium and calcium channel function and pharmacological modulation at the atomic level. These studies now define the chemical basis for electrical signaling and provide templates for future development of new therapeutic agents for a range of neurological and cardiovascular diseases.
电压门控钠离子通道在神经和肌肉中引发动作电位，而电压门控钙离子通道则将质膜的去极化与细胞内事件（如分泌、收缩、突触传递和基因表达）偶联。在这篇综述和观点文章中，我总结了早期的工作，这些工作导致了钠和钙通道的蛋白亚基的鉴定、纯化、功能重建和氨基酸序列的确定，并表明它们的孔形成亚基密切相关。通过抗体作图、定点突变和电生理记录的数十年研究，得出了涉及电压依赖性激活和失活、离子渗透和选择性以及药物调节的氨基酸残基的详细二维结构-功能图谱。最近，通过 X 射线晶体学和低温电子显微镜的高分辨率三维结构测定，揭示了钠和钙通道功能以及在原子水平上药物调节的结构基础。这些研究现在定义了电信号的化学基础，并为未来开发一系列神经和心血管疾病的新型治疗药物提供了模板。
