Department of Biomedical Engineering, Washington University, St. Louis, MO 63130.
Center for the Investigation of Membrane Excitability Disorders, Washington University, St. Louis, MO 63130.
Proc Natl Acad Sci U S A. 2021 May 18;118(20). doi: 10.1073/pnas.2024215118.
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. I (KCNQ1+KCNE1), 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 I channel. Here, we show that C28 specifically shifted I VSD activation in ventricle to more negative voltages and reversed the 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 I 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.
心律失常是全球范围内导致心源性猝死的最常见原因。心室动作电位时程（APD）延长，无论是先天的还是通过病理或药理手段，都会导致危及生命的室性心律失常，尖端扭转型室性心动过速。I 型（KCNQ1+KCNE1）缓慢激活的 K 电流在动作电位复极中起作用。在这项研究中，我们通过将化合物对接至 I 通道的电压感应域（VSD），在计算机上对化学文库进行了筛选。我们发现 C28 特异性地将 I VSD 激活向左移，使心室的电压更负，从而逆转了药物引起的 APD 延长。在相同剂量下，C28 不会引起心室或心房正常 APD 的显著变化。这项研究为 I VSD 激活的计算预测提供了证据，这可能是治疗各种 APD 延长的潜在方法。这一结果可能会扩大目前可能引发心律失常的无数种已批准药物的治疗效果。
