Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD) either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs, a slowly activating K+ current plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage sensing domain (VSD) of the IKs channel. Here we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.

中文翻译：

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调节心脏钾通道的电压传感器显示抗心律不齐的作用

心脏心律不齐是全世界心源性猝死的最常见原因。先天性地或通过病理学或药理学方法延长心室动作电位持续时间（APD），容易导致危及生命的室性心律失常，Torsade de Pointes。IKs，缓慢激活的K +电流在动作电位复极化中起作用。在这项研究中，我们通过将化合物对接至IKs通道的电压感应域（VSD），筛选了计算机上的化学文库。在这里，我们显示C28专门将IKs VSD激活在心室中转移到更多的负电压，并逆转了药物诱导的APD延长。在相同剂量下，C28不会在心室或心房中引起正常APD的显着变化。这项研究提供证据支持IKs VSD激活的计算预测，作为所有形式APD延长的潜在治疗方法。这一结果可能会扩大目前可能触发心律不齐的多种目前批准的药物的治疗效果。