1. Structural Biology and Molecular Biophysics
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Graded Ca2+/calmodulin-dependent coupling of voltage-gated CaV1.2 channels

  1. Rose E Dixon
  2. Claudia M Moreno
  3. Can Yuan
  4. Ximena Opitz-Araya
  5. Marc D Binder
  6. Manuel F Navedo
  7. Luis F Santana  Is a corresponding author
  1. University of Washington, United States
  2. University of California, Davis, United States
Research Article
  • Cited 26
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Cite this article as: eLife 2015;4:e05608 doi: 10.7554/eLife.05608

Abstract

In the heart, reliable activation of Ca2+ release from the sarcoplasmic reticulum during the plateau of the ventricular action potential requires synchronous opening of multiple CaV1.2 channels. Yet the mechanisms that coordinate this simultaneous opening during every heartbeat are unclear. Here, we demonstrate that CaV1.2 channels form clusters that undergo dynamic, reciprocal, allosteric interactions. This 'functional coupling' facilitates Ca2+ influx by increasing activation of adjoined channels and occurs through C-terminal-to-C-terminal interactions. These interactions are initiated by binding of incoming Ca2+ to calmodulin (CaM) and proceed through Ca2+/CaM binding to the CaV1.2 pre-IQ domain. Coupling fades as [Ca2+]i decreases, but persists longer than the current that evoked it, providing evidence for 'molecular memory'. Our findings suggest a model for CaV1.2 channel gating and Ca2+-influx amplification that unifies diverse observations about Ca2+ signaling in the heart, and challenges the long-held view that voltage-gated channels open and close independently.

Article and author information

Author details

  1. Rose E Dixon

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Claudia M Moreno

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Can Yuan

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ximena Opitz-Araya

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Marc D Binder

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Manuel F Navedo

    Department of Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Luis F Santana

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    For correspondence
    santana@uw.edu
    Competing interests
    The authors declare that no competing interests exist.

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 (#3374-01) of the University of Washington.

Reviewing Editor

  1. Richard Aldrich, The University of Texas at Austin, United States

Publication history

  1. Received: November 13, 2014
  2. Accepted: February 23, 2015
  3. Accepted Manuscript published: February 25, 2015 (version 1)
  4. Version of Record published: March 17, 2015 (version 2)

Copyright

© 2015, Dixon 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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