TY - JOUR
T1 - ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling
AU - Hou, Panpan
AU - Shi, Jingyi
AU - White, Kelli Mc Farland
AU - Gao, Yuan
AU - Cui, Jianmin
N1 - Funding Information:
We thank Po Wei Kang for reading and revising the manuscript. We also thank Prof. Jeanne Ner-bonne for helpful discussion. This work was supported by R01 NS092570 and R01 HL126774 (to JC), and by AHA 18POST34030203 (to PH).
Funding Information:
National Institute of Neurological Disorders and Stroke R01 NS092570 Jianmin Cui National Heart, Lung, and Blood Institute R01 HL126774 Jianmin Cui American Heart Association AHA 18POST34030203 Panpan Hou The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© Hou et al.
PY - 2019/7
Y1 - 2019/7
N2 - Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form IKs channels that regulate heart rhythm. KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Here, we tested modulations of human KCNQ1 channels by an activator ML277 in Xenopus oocytes. It exclusively changes the pore opening properties of the AO state without altering the IO state, but does not affect VSD activation. These observations support a distinctive mechanism responsible for the VSD-pore coupling at the AO state that is sensitive to ML277 modulation. ML277 provides insights and a tool to investigate the gating mechanism of KCNQ1 channels, and our study reveals a new strategy for treating long QT syndrome by specifically enhancing the AO state of native IKs currents.
AB - Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form IKs channels that regulate heart rhythm. KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Here, we tested modulations of human KCNQ1 channels by an activator ML277 in Xenopus oocytes. It exclusively changes the pore opening properties of the AO state without altering the IO state, but does not affect VSD activation. These observations support a distinctive mechanism responsible for the VSD-pore coupling at the AO state that is sensitive to ML277 modulation. ML277 provides insights and a tool to investigate the gating mechanism of KCNQ1 channels, and our study reveals a new strategy for treating long QT syndrome by specifically enhancing the AO state of native IKs currents.
UR - http://www.scopus.com/inward/record.url?scp=85071065672&partnerID=8YFLogxK
U2 - 10.7554/eLife.48576
DO - 10.7554/eLife.48576
M3 - Article
C2 - 31329101
AN - SCOPUS:85071065672
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e48576
ER -