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Cooperative and acute inhibitionby multiple C-terminal motifs of L-type Ca2+ channels

  1. Nan Liu
  2. Yaxiong Yang
  3. Lin Ge
  4. Min Liu
  5. Henry M Colecraft
  6. Xiaodong Liu  Is a corresponding author
  1. Tsinghua University, China
  2. Columbia University, United States
Research Article
  • Cited 4
  • Views 1,914
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Cite this article as: eLife 2017;6:e21989 doi: 10.7554/eLife.21989

Abstract

Inhibitions and antagonists of L-type Ca2+ channels are important to both research and therapeutics. Here, we report C-terminus mediated inhibition (CMI) for CaV1.3 that multiple motifs coordinate to tune down Ca2+ current and Ca2+ influx toward the lower limits determined by end-stage CDI (Ca2+-dependent inactivation). Among IQV (preIQ3-IQ domain), PCRD and DCRD (proximal or distal C-terminal regulatory domain), spatial closeness of any two modules, e.g., by constitutive fusion, facilitates the trio to form the complex, compete against calmodulin, and alter the gating. Acute CMI by rapamycin-inducible heterodimerization helps reconcile the concurrent activation/inactivation attenuations to ensure Ca2+ influx is reduced, in that Ca2+ current activated by depolarization is potently (~65%) inhibited at the peak (full activation), but not later on (end-stage inactivation, ~300 ms). Meanwhile, CMI provides a new paradigm to develop CaV1 inhibitors, the therapeutic potential of which is implied by computational modeling of CaV1.3 dysregulations related to Parkinson's disease.

Article and author information

Author details

  1. Nan Liu

    X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9606-4732
  2. Yaxiong Yang

    X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Lin Ge

    X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Min Liu

    X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Henry M Colecraft

    Department of Physiology and Cellular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiaodong Liu

    X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China
    For correspondence
    liuxiaodong@tsinghua.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3171-9611

Funding

National Natural Science Foundation of China (81171382,31370822,81371604)

  • Xiaodong Liu

Natural Science Foundation of Beijing Municipality (7142089)

  • Xiaodong Liu

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

Reviewing Editor

  1. Kenton J Swartz, National Institutes of Health, United States

Publication history

  1. Received: October 5, 2016
  2. Accepted: January 5, 2017
  3. Accepted Manuscript published: January 6, 2017 (version 1)
  4. Version of Record published: January 30, 2017 (version 2)

Copyright

© 2017, Liu 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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