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.

Data availability

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.

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.

Metrics

  • 1,324
    views
  • 235
    downloads
  • 7
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Citations by DOI

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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