1. Biochemistry and Chemical Biology
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Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels

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Cite this article as: eLife 2016;5:e21143 doi: 10.7554/eLife.21143

Abstract

The auxiliary α2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α2 and δ. We now show, using α2δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α2δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α2δ. Uncleaved α2δ does not support trafficking of CaV2.2 channel complexes into neuronal processes, and inhibits Ca2+ entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. We propose a model whereby uncleaved α2δ subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of α2δ then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes.

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Author details

  1. Ivan Kadurin

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    For correspondence
    i.kadurin@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Laurent Ferron

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Simon W Rothwell

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. James O Meyer

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Leon R Douglas

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Claudia S Bauer

    Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Beatrice Lana

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Wojciech Margas

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Orpheas Alexopoulos

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Manuela Nieto-Rostro

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Wendy S Pratt

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Annette C Dolphin

    Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    For correspondence
    a.dolphin@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4626-4856

Funding

Wellcome (098360/Z/12/Z)

  • Ivan Kadurin
  • Laurent Ferron
  • Simon W Rothwell
  • Wojciech Margas
  • Manuela Nieto-Rostro

Medical Research Council (G0901758, G0801756, MR/J013285/1)

  • Laurent Ferron
  • Leon R Douglas
  • Claudia S Bauer

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

Reviewing Editor

  1. Mary B Kennedy, California Institute of Technology, United States

Publication history

  1. Received: August 31, 2016
  2. Accepted: October 25, 2016
  3. Accepted Manuscript published: October 26, 2016 (version 1)
  4. Version of Record published: November 2, 2016 (version 2)
  5. Version of Record updated: November 8, 2016 (version 3)

Copyright

© 2016, Kadurin 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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