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Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects [Biophysics and Computational Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-05-18 , DOI: 10.1073/pnas.2024215118
Yangyang Lin 1, 2, 3 , Sam Z Grinter 4, 5, 6 , Zhongju Lu 7 , Xianjin Xu 4 , Hong Zhan Wang 7 , Hongwu Liang 1, 2, 3 , Panpan Hou 1, 2, 3 , Junyuan Gao 7 , Chris Clausen 7 , Jingyi Shi 1, 2, 3 , Wenshan Zhao 1, 2, 3 , Zhiwei Ma 4, 6 , Yongfeng Liu 1, 2, 3 , Kelli McFarland White 1, 2, 3 , Lu Zhao 1, 2, 3 , Po Wei Kang 1, 2, 3 , Guohui Zhang 1, 2, 3 , Ira S Cohen 8 , Xiaoqin Zou 5, 6, 9, 10 , Jianmin Cui 2, 3, 11
Affiliation  

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 (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 IKs channel. Here, we show that C28 specifically shifted IKs 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 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:

调节心脏钾通道的电压传感器显示出抗心律失常作用 [生物物理学和计算生物学]

心律失常是全世界心源性猝死的最常见原因。先天性或通过病理或药理学手段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。I Ks (KCNQ1+KCNE1) 是一种缓慢激活的 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到 I Ks通道的电压感应域 (VSD) 来筛选化学文库。在这里,我们展示了 C28 特别地移动了 I Ks心室中的 VSD 激活到更多的负电压并逆转药物引起的 APD 延长。在相同剂量下,C28 不会引起心室或心房正常 APD 的显着变化。这项研究提供了支持 I Ks VSD 激活的计算预测作为所有形式的 APD 延长的潜在治疗方法的证据。这一结果可以扩大目前批准的无数可能引发心律失常的药物的治疗效果。

更新日期:2021-05-15
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