Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels

Abstract

Neuronal KCNQ channels mediate the M-current, a key regulator of membrane excitability in the central and peripheral nervous systems. Mutations in KCNQ2 channels cause severe neurodevelopmental disorders, including epileptic encephalopathies. However, the impact that different mutations have on channel function remains poorly defined, largely because of our limited understanding of the voltage sensing mechanisms that trigger channel gating. Here, we define parameters of voltage sensor movements in wt-KCNQ2 and channels bearing epilepsy-associated mutations using cysteine accessibility and voltage clamp fluorometry (VCF). Cysteine modification reveals that a stretch of 8-9 amino acids in the S4 become exposed upon VSD activation of KCNQ2 channels. VCF shows that the voltage dependence and the time course of S4 movement and channel opening/closing closely correlate. VCF reveals different mechanisms by which different epilepsy-associated mutations affect KCNQ2 channel voltage-dependent gating. This study provides insight into KCNQ2 channel function, which will aid in uncovering the mechanisms underlying channelopathies.

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All data generated or analyzed during this study are included in the manuscript and supplementary information (all combined in one pdf file).

Article and author information

Author details

  1. Michaela A Edmond

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Andy Hinojo-Perez

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaoan Wu

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2098-7298
  4. Marta E Perez Rodriguez

    2Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rene Barro-Soria

    2Department of Physiology and Biophysics, University of Miami, Miami, United States
    For correspondence
    rbarro@miami.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4804-2739

Funding

National Institute of Neurological Disorders and Stroke (R01NS110847)

  • Rene Barro-Soria

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jon T Sack, University of California Davis School of Medicine, United States

Version history

  1. Received: January 13, 2022
  2. Preprint posted: January 21, 2022 (view preprint)
  3. Accepted: May 31, 2022
  4. Accepted Manuscript published: June 1, 2022 (version 1)
  5. Accepted Manuscript updated: June 13, 2022 (version 2)
  6. Version of Record published: June 14, 2022 (version 3)

Copyright

© 2022, Edmond 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. Michaela A Edmond
  2. Andy Hinojo-Perez
  3. Xiaoan Wu
  4. Marta E Perez Rodriguez
  5. Rene Barro-Soria
(2022)
Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels
eLife 11:e77030.
https://doi.org/10.7554/eLife.77030

Share this article

https://doi.org/10.7554/eLife.77030

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