Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

Yangyang Lin; Sam Z. Grinter; Zhongju Lu; Xianjin Xu; Hong Zhan Wang; Hongwu Liang; Panpan Hou; Junyuan Gao; Chris Clausen; Jingyi Shi; Wenshan Zhao; Zhiwei Ma; Yongfeng Liu; McFarland White Kelli McFarland White; Lu Zhao; Po Wei Kang; Guohui Zhang; Ira S. Cohen; Xiaoqin Zou; Jianmin Cui

doi:10.1073/pnas.2024215118

Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

Yangyang Lin, Sam Z. Grinter, Zhongju Lu, Xianjin Xu, Hong Zhan Wang, Hongwu Liang, Panpan Hou, Junyuan Gao, Chris Clausen, Jingyi Shi, Wenshan Zhao, Zhiwei Ma, Yongfeng Liu, McFarland White Kelli McFarland White, Lu Zhao, Po Wei Kang, Guohui Zhang, Ira S. Cohen, Xiaoqin Zou, Jianmin Cui

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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. I_Ks(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_Kschannel. Here, we show that C28 specifically shifted I_KsVSD 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_KsVSD 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.

Original language	English
Article number	e2024215118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	20
DOIs	https://doi.org/10.1073/pnas.2024215118
State	Published - May 18 2021

Keywords

Antiarrhythmia
C28
I
KCNQ1
Voltage sensor domain

Access to Document

10.1073/pnas.2024215118

Cite this

Lin, Y., Grinter, S. Z., Lu, Z., Xu, X., Wang, H. Z., Liang, H., Hou, P., Gao, J., Clausen, C., Shi, J., Zhao, W., Ma, Z., Liu, Y., Kelli McFarland White, M. W., Zhao, L., Kang, P. W., Zhang, G., Cohen, I. S., Zou, X., & Cui, J. (2021). Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects. Proceedings of the National Academy of Sciences of the United States of America, 118(20), Article e2024215118. https://doi.org/10.1073/pnas.2024215118

@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",

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",

}

Lin, Y, Grinter, SZ, Lu, Z, Xu, X, Wang, HZ, Liang, H, Hou, P, Gao, J, Clausen, C, Shi, J, Zhao, W, Ma, Z, Liu, Y, Kelli McFarland White, MW, Zhao, L, Kang, PW, Zhang, G, Cohen, IS, Zou, X & Cui, J 2021, 'Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 20, e2024215118. https://doi.org/10.1073/pnas.2024215118

TY - JOUR

T1 - Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

AU - Lin, Yangyang

AU - Grinter, Sam Z.

AU - Lu, Zhongju

AU - Xu, Xianjin

AU - Wang, Hong Zhan

AU - Liang, Hongwu

AU - Hou, Panpan

AU - Gao, Junyuan

AU - Clausen, Chris

AU - Shi, Jingyi

AU - Zhao, Wenshan

AU - Ma, Zhiwei

AU - Liu, Yongfeng

AU - Kelli McFarland White, McFarland White

AU - Zhao, Lu

AU - Kang, Po Wei

AU - Zhang, Guohui

AU - Cohen, Ira S.

AU - Zou, Xiaoqin

AU - Cui, Jianmin

PY - 2021/5/18

Y1 - 2021/5/18

N2 - 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.

AB - 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.

KW - Antiarrhythmia

KW - C28

KW - I

KW - KCNQ1

KW - Voltage sensor domain

UR - http://www.scopus.com/inward/record.url?scp=85106257867&partnerID=8YFLogxK

U2 - 10.1073/pnas.2024215118

DO - 10.1073/pnas.2024215118

M3 - Article

C2 - 33990467

AN - SCOPUS:85106257867

SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 20

M1 - e2024215118

ER -

Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this