Catterall William A, Swanson Teresa M
Department of Pharmacology, University of Washington, Seattle, Washington
Department of Pharmacology, University of Washington, Seattle, Washington.
Mol Pharmacol. 2015 Jul;88(1):141-50. doi: 10.1124/mol.114.097659. Epub 2015 Apr 6.
Voltage-gated sodium channels initiate action potentials in nerve, muscle, and other electrically excitable cells. Voltage-gated calcium channels are activated by depolarization during action potentials, and calcium influx through them is the key second messenger of electrical signaling, initiating secretion, contraction, neurotransmission, gene transcription, and many other intracellular processes. Drugs that block sodium channels are used in local anesthesia and the treatment of epilepsy, bipolar disorder, chronic pain, and cardiac arrhythmia. Drugs that block calcium channels are used in the treatment of epilepsy, chronic pain, and cardiovascular disorders, including hypertension, angina pectoris, and cardiac arrhythmia. The principal pore-forming subunits of voltage-gated sodium and calcium channels are structurally related and likely to have evolved from ancestral voltage-gated sodium channels that are widely expressed in prokaryotes. Determination of the structure of a bacterial ancestor of voltage-gated sodium and calcium channels at high resolution now provides a three-dimensional view of the binding sites for drugs acting on sodium and calcium channels. In this minireview, we outline the different classes of sodium and calcium channel drugs, review studies that have identified amino acid residues that are required for their binding and therapeutic actions, and illustrate how the analogs of those key amino acid residues may form drug-binding sites in three-dimensional models derived from bacterial channels.
电压门控钠通道在神经、肌肉和其他电可兴奋细胞中引发动作电位。电压门控钙通道在动作电位期间通过去极化被激活，通过它们的钙内流是电信号传导的关键第二信使，引发分泌、收缩、神经传递、基因转录和许多其他细胞内过程。阻断钠通道的药物用于局部麻醉以及癫痫、双相情感障碍、慢性疼痛和心律失常的治疗。阻断钙通道的药物用于癫痫、慢性疼痛和心血管疾病的治疗，包括高血压、心绞痛和心律失常。电压门控钠通道和钙通道的主要孔形成亚基在结构上相关，并且可能从在原核生物中广泛表达的祖先电压门控钠通道进化而来。现在，高分辨率测定电压门控钠通道和钙通道的细菌祖先的结构，提供了作用于钠通道和钙通道的药物结合位点的三维视图。在本综述中，我们概述了不同类别的钠通道和钙通道药物，回顾了已确定其结合和治疗作用所需氨基酸残基的研究，并说明了这些关键氨基酸残基的类似物如何在源自细菌通道的三维模型中形成药物结合位点。
