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

Abstract

Significance C28, a chemical compound identified by computational screening, selectively facilitates voltage-dependent activation of a cardiac potassium ion channel, IKs. This compound reverses drug-induced prolongation of the electric signals across the cardiac cell membrane known as action potentials (APs) but minimally affects the normal AP at the same dosage. This outcome supports a computational prediction that enhancing voltage-dependent activation of IKs could be a potential therapy for AP prolongation. This therapy would increase the safety and expand the therapeutic efficacy of many currently approved drugs that induce AP prolongation, which can trigger life-threatening cardiac arrhythmias. 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.