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

  1. Panpan Hou
  2. Jingyi Shi
  3. Kelli McFarland White
  4. Yuan Gao
  5. Jianmin Cui  Is a corresponding author
  1. Washington University in St Louis, United States
  2. Tencent AI lab, China

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 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.

Data availability

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

Article and author information

Author details

  1. 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.
  2. 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.
  3. 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.
  4. Yuan Gao

    Tencent AI lab, Shenzhen, China
    Competing interests
    No competing interests declared.
  5. 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.
    ORCID icon "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).

Reviewing Editor

  1. Baron Chanda, University of Wisconsin-Madison, United States

Publication history

  1. Received: May 21, 2019
  2. Accepted: July 22, 2019
  3. Accepted Manuscript published: July 22, 2019 (version 1)
  4. Version of Record published: August 6, 2019 (version 2)

Copyright

© 2019, Hou et al.

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.

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  1. Panpan Hou
  2. Jingyi Shi
  3. Kelli McFarland White
  4. Yuan Gao
  5. Jianmin Cui
(2019)
ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling
eLife 8:e48576.
https://doi.org/10.7554/eLife.48576
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