1. Structural Biology and Molecular Biophysics
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ER-luminal [Ca2+] regulation of InsP3 receptor gating mediated by an ER-luminal peripheral Ca2+-binding protein

  1. Horia Vais
  2. Min Wang
  3. Karthik Mallilankaraman
  4. Riley Payne
  5. Chris McKennan
  6. Jeffrey T Lock
  7. Lynn A Spruce
  8. Carly Fiest
  9. Matthew Y Chan
  10. Ian Parker
  11. Steven H Seeholzer
  12. J Kevin Foskett  Is a corresponding author
  13. Don-On Daniel Mak
  1. University of Pennsylvania, United States
  2. University of Pittsburgh, United States
  3. University of California, Irvine, United States
  4. Children's hospital of Philadelphia, United States
Research Article
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Cite this article as: eLife 2020;9:e53531 doi: 10.7554/eLife.53531

Abstract

Modulating cytoplasmic Ca2+ concentration ([Ca2+]i) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP3R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca2+ concentration ([Ca2+]ER) is poorly understood and controversial. We discovered that the InsP3R is regulated by a peripheral membrane-associated ER-luminal protein that strongly inhibits the channel in the presence of high, physiological [Ca2+]ER. The widely-expressed Ca2+-binding protein annexin A1 (ANXA1) is present in the nuclear envelope lumen and, through interaction with a luminal region of the channel, can modify high-[Ca2+]ER inhibition of InsP3R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP3-mediated Ca2+ signaling events. Thus, [Ca2+]ER is a major regulator of InsP3R channel activity and InsP3R-mediated [Ca2+]i signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca2+-binding protein, likely ANXA1.

Article and author information

Author details

  1. Horia Vais

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Min Wang

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Karthik Mallilankaraman

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9492-9050
  4. Riley Payne

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Chris McKennan

    Department of Statistics, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jeffrey T Lock

    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1522-3189
  7. Lynn A Spruce

    Proteomics Core, Children's hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Carly Fiest

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1162-712X
  9. Matthew Y Chan

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ian Parker

    Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Steven H Seeholzer

    Proteomics Core, Children's hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. J Kevin Foskett

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    For correspondence
    foskett@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8854-0268
  13. Don-On Daniel Mak

    Department of Physiology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (R37GM56328)

  • J Kevin Foskett

National Institutes of Health (R01GM114042)

  • Don-On Daniel Mak

National Institutes of Health (GM048071)

  • Ian Parker

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

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Publication history

  1. Received: November 12, 2019
  2. Accepted: May 15, 2020
  3. Accepted Manuscript published: May 18, 2020 (version 1)
  4. Version of Record published: May 29, 2020 (version 2)

Copyright

© 2020, Vais 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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