Shank is a dose-dependent regulator of Cav1 calcium current and CREB target expression

  1. Edward Pym
  2. Nikhil Sasidharan
  3. Katherine L Thompson-Peer
  4. David J Simon
  5. Anthony Anselmo
  6. Ruslan I Sadreyev
  7. Qi Hall
  8. Stephen Nurrish
  9. Joshua M Kaplan  Is a corresponding author
  1. Massachusetts General Hospital, United States
  2. University of California, San Francisco, United States
  3. Stanford School of Medicine, United States

Abstract

Shank is a post-synaptic scaffolding protein that has many binding partners. Shank mutations and copy number variations (CNVs) are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. It is not known which Shank binding partners are responsible for these defects. Here we show that the C. elegans SHN-1/Shank binds L-type calcium channels and that increased and decreased shn-1 gene dosage alter L-channel current and activity-induced expression of a CRH-1/CREB transcriptional target (gem-4 Copine), which parallels the effects of human Shank copy number variations (CNVs) on Autism spectrum disorders and schizophrenia. These results suggest that an important function of Shank proteins is to regulate L-channel current and activity induced gene expression.

Article and author information

Author details

  1. Edward Pym

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

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Katherine L Thompson-Peer

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4200-3870
  4. David J Simon

    Department of Neurobiology, Stanford School of Medicine, Palo Alto, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Anthony Anselmo

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ruslan I Sadreyev

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

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

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. 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 Institute of Neurological Disorders and Stroke (NS32196)

  • Joshua M Kaplan

Simons Foundation (SF273555)

  • Joshua M Kaplan

Nancy Lurie Marks Family Foundation

  • Edward Pym

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: June 19, 2016
  2. Accepted: April 18, 2017
  3. Accepted Manuscript published: May 6, 2017 (version 1)
  4. Version of Record published: May 15, 2017 (version 2)

Copyright

© 2017, Pym 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. Edward Pym
  2. Nikhil Sasidharan
  3. Katherine L Thompson-Peer
  4. David J Simon
  5. Anthony Anselmo
  6. Ruslan I Sadreyev
  7. Qi Hall
  8. Stephen Nurrish
  9. Joshua M Kaplan
(2017)
Shank is a dose-dependent regulator of Cav1 calcium current and CREB target expression
eLife 6:e18931.
https://doi.org/10.7554/eLife.18931

Share this article

https://doi.org/10.7554/eLife.18931

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