ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling

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Abstract

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 I_Ks channels that regulate heart rhythm. KCNE1 suppresses the IO state so that the I_Ks 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 I_Ks currents.

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All data generated or analysed during this study are included in the manuscript.

Article and author information

Author details

Panpan Hou

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States

Competing interests
No competing interests declared.
Jingyi Shi

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States

Competing interests
Jingyi Shi, is a co-founder of a startup company VivoCor LLC, which is targeting IKs for the treatment of cardiac arrhythmia.
Kelli McFarland White

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States

Competing interests
No competing interests declared.
Yuan Gao

Tencent AI lab, Shenzhen, China

Competing interests
No competing interests declared.
Jianmin Cui

Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States

For correspondence
jcui@wustl.edu

Competing interests
Jianmin Cui, is a co-founder of a startup company VivoCor LLC, which is targeting IKs for the treatment of cardiac arrhythmia.

"This ORCID iD identifies the author of this article:" 0000-0001-7694-2262

Funding

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.

Ethics

Animal experimentation: Oocytes (at stage V or VI) were obtained from Xenopus laevis by laparotomy surgery, following the protocol approved by the Washington University Animal Studies Committee (Protocol #20160046).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.