Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels
- University College London, United Kingdom
- University of Sheffield, United Kingdom
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
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.
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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Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels
eLife 5:e21143.
https://doi.org/10.7554/eLife.21143
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