1. Neuroscience

Proteolytic maturation of α2δ controls the probability of synaptic vesicular release

  1. Laurent Ferron  Is a corresponding author
  2. Ivan Kadurin
  3. Annette C Dolphin
  1. University College London, United Kingdom
https://doi.org/10.7554/eLife.37507
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  1. Laurent Ferron
  2. Ivan Kadurin
  3. Annette C Dolphin
(2018)
Proteolytic maturation of α2δ controls the probability of synaptic vesicular release
eLife 7:e37507.
https://doi.org/10.7554/eLife.37507
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Abstract

Auxiliary α2δ subunits are important proteins for trafficking of voltage-gated calcium channels (CaV) at the active zones of synapses. We have previously shown that the post-translational proteolytic cleavage of α2δ is essential for their modulatory effects on the trafficking of N-type (CaV2.2) calcium channels (Kadurin et al. 2016). We extend these results here by showing that the probability of presynaptic vesicular release is reduced when an uncleaved α2δ is expressed in rat neurons and that this inhibitory effect is reversed when cleavage of α2δ is restored. We also show that asynchronous release is influenced by the maturation of α2δ-1, highlighting the role of CaV channels in this component of vesicular release. We present additional evidence that CaV2.2 co-immunoprecipitates preferentially with cleaved wild-type α2δ. Our data indicate that the proteolytic maturation increases the association of α2δ-1 with CaV channel complex and is essential for its function on synaptic release.

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All data generated or analysed during this study are included in the manuscript.

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Author details

  1. Laurent Ferron

    Deprtment of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    For correspondence
    l.ferron@ucl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2547-7417

  2. Ivan Kadurin

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

  3. Annette C Dolphin

    Deprtment of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    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)

  • Annette C Dolphin

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

Ethics

Animal experimentation: All experiments were performed in accordance with the Home Office Animals (Scientific procedures) Act 1986, UK, using a Schedule 1 method.

Copyright

© 2018, Ferron 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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  1. Laurent Ferron
  2. Ivan Kadurin
  3. Annette C Dolphin
(2018)
Proteolytic maturation of α2δ controls the probability of synaptic vesicular release
eLife 7:e37507.
https://doi.org/10.7554/eLife.37507

Share this article

https://doi.org/10.7554/eLife.37507

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Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience

    Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels

    Ivan Kadurin, Laurent Ferron ... Annette C Dolphin
    Research Article Updated

    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.