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Proteolytic maturation of alpha(2)delta represents a checkpoint for activation and neuronal trafficking of latent calcium channels

Kadurin, I; Ferron, L; Rothwell, SW; Meyer, JO; Douglas, LR; Bauer, CS; Lana, B; ... Dolphin, AC; + view all (2016) Proteolytic maturation of alpha(2)delta represents a checkpoint for activation and neuronal trafficking of latent calcium channels. ELIFE , 5 (ARTN e21) 10.7554/eLife.21143. Green open access

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Abstract

The auxiliary a2d subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides a2 and d. We now show, using a2d 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 a2d inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of a2d, voltage-dependent activation of channels is promoted, independent from the trafficking role of a2d. Uncleaved a2d 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 a2d subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of a2d then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes.

Type: Article
Title: Proteolytic maturation of alpha(2)delta represents a checkpoint for activation and neuronal trafficking of latent calcium channels
Open access status: An open access version is available from UCL Discovery
DOI: 10.7554/eLife.21143
Publisher version: http://dx.doi.org/10.7554/eLife.21143
Additional information: © Copyright Kadurin et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biology, Life Sciences & Biomedicine - Other Topics, GATED CA2+ CHANNELS, UP-REGULATION, FUNCTIONAL-PROPERTIES, TRUNCATED CONSTRUCTS, AUXILIARY SUBUNITS, SKELETAL-MUSCLE, SENSORY NEURONS, NERVE INJURY, BETA-SUBUNIT, PROTEIN
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1527233
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