Proteolytic maturation of α2δ controls the probability of synaptic vesicular release

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Abstract

Auxiliary α₂δ subunits are important proteins for trafficking of voltage-gated calcium channels (Ca_V) 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 (Ca_V2.2) 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 Ca_V channels in this component of vesicular release. We present additional evidence that Ca_V2.2 co-immunoprecipitates preferentially with cleaved wild-type α₂δ. Our data indicate that the proteolytic maturation increases the association of α₂δ-1 with Ca_V 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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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.

"This ORCID iD identifies the author of this article:" 0000-0002-2547-7417
Ivan Kadurin

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

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Reviewing Editor

Mary B Kennedy, California Institute of Technology, United States

Ethics

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

Version history

Received: April 16, 2018
Accepted: June 18, 2018
Accepted Manuscript published: June 19, 2018 (version 1)
Version of Record published: July 3, 2018 (version 2)

Copyright

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.