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Proc Natl Acad Sci U S A
2021 May 18;11820:. doi: 10.1073/pnas.2024215118.
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Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects.
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
,
White KM
,
Zhao L
,
Kang PW
,
Zhang G
,
Cohen IS
,
Zou X
,
Cui J
.
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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.
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