Gating Mechanisms Underlying Deactivation Slowing by Two KCNQ1 Atrial Fibrillation Mutations

Overview

Journal Sci Rep

Specialty Science

Date 2017 Apr 7

PMID 28383569

Citations 13

Authors

Gary Peng

Rene Barro-Soria

Kevin J Sampson

H Peter Larsson

Robert S Kass

Affiliations

Soon will be listed here.

Abstract

KCNQ1 is a voltage-gated potassium channel that is modulated by the beta-subunit KCNE1 to generate I, the slow delayed rectifier current, which plays a critical role in repolarizing the cardiac action potential. Two KCNQ1 gain-of-function mutations that cause a genetic form of atrial fibrillation, S140G and V141M, drastically slow I deactivation. However, the underlying gating alterations remain unknown. Voltage clamp fluorometry (VCF) allows simultaneous measurement of voltage sensor movement and current through the channel pore. Here, we use VCF and kinetic modeling to determine the effects of mutations on channel voltage-dependent gating. We show that in the absence of KCNE1, S140G, but not V141M, directly slows voltage sensor movement, which indirectly slows current deactivation. In the presence of KCNE1, both S140G and V141M slow pore closing and alter voltage sensor-pore coupling, thereby slowing current deactivation. Our results suggest that KCNE1 can mediate changes in pore movement and voltage sensor-pore coupling to slow I deactivation and provide a key step toward developing mechanism-based therapies.

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