Title

IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits

ORCiD

0000-0002-6489-4651

Document Type

Article

Publication Title

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

ISSN

1091-6490

Volume

110

Issue

7

DOI

10.1073/pnas.1222616110

First Page

559

Last Page

566

Publication Date

2-12-2013

Abstract

Human I(Ks) channels activate slowly with the onset of cardiac action potentials to repolarize the myocardium. I(Ks) channels are composed of KCNQ1 (Q1) pore-forming subunits that carry S4 voltage-sensor segments and KCNE1 (E1) accessory subunits. Together, Q1 and E1 subunits recapitulate the conductive and kinetic properties of I(Ks). How E1 modulates Q1 has been unclear. Investigators have variously posited that E1 slows the movement of S4 segments, slows opening and closing of the conduction pore, or modifies both aspects of electromechanical coupling. Here, we show that Q1 gating current can be resolved in the absence of E1, but not in its presence, consistent with slowed movement of the voltage sensor. E1 was directly demonstrated to slow S4 movement with a fluorescent probe on the Q1 voltage sensor. Direct correlation of the kinetics of S4 motion and ionic current indicated that slowing of sensor movement by E1 was both necessary and sufficient to determine the slow-activation time course of I(Ks).