@article{e9061e4d7def42bc8bf9d5eea84d7ac9,
title = "Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects",
abstract = "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 IKschannel. Here, we show that C28 specifically shifted IKsVSD 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 IKsVSD 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.",
keywords = "Antiarrhythmia, C28, I, KCNQ1, Voltage sensor domain",
author = "Yangyang Lin and Grinter, {Sam Z.} and Zhongju Lu and Xianjin Xu and Wang, {Hong Zhan} and Hongwu Liang and Panpan Hou and Junyuan Gao and Chris Clausen and Jingyi Shi and Wenshan Zhao and Zhiwei Ma and Yongfeng Liu and {Kelli McFarland White}, {McFarland White} and Lu Zhao and Kang, {Po Wei} and Guohui Zhang and Cohen, {Ira S.} and Xiaoqin Zou and Jianmin Cui",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Zhaobin Gao for providing the complementary DNA of KTQ and KTV fusion proteins. Nien-Du Yang at Washington University helped in some experiments and data analyses. This work was supported by Grants R01 HL126774 (J.C., X.Z., and I.S.C.), R01 DK108989 (I.S.C.), R01 GM109980 (X.Z.), and R35GM136409 (X.Z.) from NIH and 13GRNT16990076 (X.Z. and J.S.) from the American Heart Association (Midwest Affiliate). Y. Lin was a visiting student supported by the China Scholarship Council (201206380052) via the Sixth Affiliated Hospital of Sun Yat-sen University, China; S.Z.G. was also supported through the National Library of Medicine Biomedical Informatics Research Training Program T15 LM07089. The computations were performed on the high-performance computing (HPC) infrastructure supported by the NSF Division of Computer and Network Systems 1429294 (PI: Chi-Ren Shyu) and the HPC resources supported by the University of Missouri Bioinformatics Consortium. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = may,
day = "18",
doi = "10.1073/pnas.2024215118",
language = "English",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "20",
}