1. Structural Biology and Molecular Biophysics
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Allosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channels

  1. Jacqueline Niu
  2. Ivy E Dick
  3. Wanjun Yang
  4. Moradeke A Bamgboye
  5. David T Yue
  6. Gordon Tomaselli
  7. Takanari Inoue  Is a corresponding author
  8. Manu Ben-Johny  Is a corresponding author
  1. Johns Hopkins University, United States
  2. University of Maryland, United States
  3. Columbia University Medical Center, United States
Research Article
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Cite this article as: eLife 2018;7:e35222 doi: 10.7554/eLife.35222

Abstract

Calmodulin (CaM) serves as a pervasive regulatory subunit of CaV1, CaV2, and NaV1 channels, exploiting a functionally-conserved carboxy-tail element to afford dynamic Ca2+-feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally-unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca2+/CaM-regulation of CaV1 and NaV1 families respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into CaV1.3 carboxy-tail, confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca2+/CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca2+/CaM signaling to individual targets.

Article and author information

Author details

  1. Jacqueline Niu

    Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ivy E Dick

    Department of Physiology, University of Maryland, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Wanjun Yang

    Department of Cardiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Moradeke A Bamgboye

    Department of Physiology, University of Maryland, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. David T Yue

    Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Gordon Tomaselli

    Department of Cardiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Takanari Inoue

    Department of Cell Biology, Johns Hopkins University, Baltimore, United States
    For correspondence
    jctinoue@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. Manu Ben-Johny

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    For correspondence
    mbj2124@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5645-0815

Funding

National Institute of Mental Health

  • David T Yue
  • Manu Ben-Johny

National Heart, Lung, and Blood Institute

  • Gordon Tomaselli
  • Manu Ben-Johny

National Science Foundation

  • Jacqueline Niu

National Institute of Neurological Disorders and Stroke

  • Ivy E Dick
  • David T Yue

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Johns Hopkins University (GP15M172). The protocol was approved by the Committee on the Ethics of Animal Experiments of the Johns Hopkins University. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Indira M Raman, Northwestern University, United States

Publication history

  1. Received: January 22, 2018
  2. Accepted: September 9, 2018
  3. Accepted Manuscript published: September 10, 2018 (version 1)
  4. Version of Record published: September 25, 2018 (version 2)

Copyright

© 2018, Niu 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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