Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihama-Boji, Yamashiro-cho, Tokushima 770-8514, Japan.
Int J Mol Sci. 2023 Nov 13;24(22):16261. doi: 10.3390/ijms242216261.
Modulation of the human Ether-à-go-go-Related Gene (hERG) channel, a crucial voltage-gated potassium channel in the repolarization of action potentials in ventricular myocytes of the heart, has significant implications on cardiac electrophysiology and can be either antiarrhythmic or proarrhythmic. For example, hERG channel blockade is a leading cause of long QT syndrome and potentially life-threatening arrhythmias, such as . Conversely, hERG channel blockade is the mechanism of action of Class III antiarrhythmic agents in terminating ventricular tachycardia and fibrillation. In recent years, it has been recognized that less proarrhythmic hERG blockers with clinical potential or Class III antiarrhythmic agents exhibit, in addition to their hERG-blocking activity, a second action that facilitates the voltage-dependent activation of the hERG channel. This facilitation is believed to reduce the proarrhythmic potential by supporting the final repolarizing of action potentials. This review covers the pharmacological characteristics of hERG blockers/facilitators, the molecular mechanisms underlying facilitation, and their clinical significance, as well as unresolved issues and requirements for research in the fields of ion channel pharmacology and drug-induced arrhythmias.
人类 Ether-à-go-go 相关基因 (hERG) 通道的调制，该通道是心脏心室肌细胞动作电位复极化中的关键电压门控钾通道，对心脏电生理学有重要影响，可能具有抗心律失常或致心律失常作用。例如，hERG 通道阻断是长 QT 综合征和潜在危及生命的心律失常（如尖端扭转型室性心动过速）的主要原因。相反，hERG 通道阻断是 III 类抗心律失常药物终止室性心动过速和颤动的作用机制。近年来，人们认识到，具有临床潜力的致心律失常性较低的 hERG 阻滞剂或 III 类抗心律失常药物除了具有 hERG 阻断活性外，还具有促进 hERG 通道电压依赖性激活的第二种作用。这种促进作用被认为通过支持动作电位的最终复极化来降低致心律失常的可能性。本综述涵盖了 hERG 阻滞剂/促进剂的药理学特征、促进作用的分子机制及其临床意义，以及离子通道药理学和药物诱导心律失常领域研究中尚未解决的问题和要求。
