Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains

  1. Luna Gao
  2. Jian Zhao
  3. Evan L. Ardiel
  4. Qi Hall
  5. Stephen Nurrish
  6. Joshua M Kaplan  Is a corresponding author
  1. Massachusetts General Hospital, United States

Abstract

Mutations altering the scaffolding protein Shank are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. Among its many binding partners, Shank directly binds CaV1 voltage activated calcium channels. Here we show that the C. elegans SHN-1/Shank promotes CaV1 coupling to calcium activated potassium channels. Mutations inactivating SHN-1, and those preventing SHN-1 binding to EGL-19/CaV1 all increase action potential durations in body muscles. Action potential repolarization is mediated by two classes of potassium channels: SHK-1/KCNA and SLO-1 and SLO-2 BK channels. BK channels are calcium-dependent, and their activation requires tight coupling to EGL-19/CaV1 channels. SHN-1's effects on AP duration are mediated by changes in BK channels. In shn-1 mutants, SLO-2 currents and channel clustering are significantly decreased in both body muscles and neurons. Finally, increased and decreased shn-1 gene copy number produce similar changes in AP width and SLO-2 current. Collectively, these results suggest that an important function of Shank is to promote microdomain coupling of BK with CaV1.

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

Article and author information

Author details

  1. Luna Gao

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jian Zhao

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Evan L. Ardiel

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Qi Hall

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephen Nurrish

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2653-9384
  6. Joshua M Kaplan

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    For correspondence
    kaplan@molbio.mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7418-7179

Funding

National Institutes of Health (NS32196)

  • Joshua M Kaplan

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

Reviewing Editor

  1. Graeme W Davis, University of California, San Francisco, United States

Version history

  1. Received: October 30, 2021
  2. Preprint posted: November 5, 2021 (view preprint)
  3. Accepted: March 9, 2022
  4. Accepted Manuscript published: March 10, 2022 (version 1)
  5. Version of Record published: March 21, 2022 (version 2)

Copyright

© 2022, Gao 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. Luna Gao
  2. Jian Zhao
  3. Evan L. Ardiel
  4. Qi Hall
  5. Stephen Nurrish
  6. Joshua M Kaplan
(2022)
Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains
eLife 11:e75140.
https://doi.org/10.7554/eLife.75140

Share this article

https://doi.org/10.7554/eLife.75140

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