We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Proteolytic maturation of α<sub>2</sub>δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels.
- Authors
Kadurin, Ivan; Ferron, Laurent; Rothwell, Simon W.; Meyer, James O.; Douglas, Leon R.; Bauer, Claudia S.; Lana, Beatrice; Margas, Wojciech; Alexopoulos, Orpheas; Nieto-Rostro, Manuela; Pratt, Wendy S.; Dolphin, Annette C.
- 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.
- Subjects
CALCIUM channels regulation; VOLTAGE-gated ion channels; PROTEOLYSIS; CELL membranes; NEURAL physiology
- Publication
eLife, 2016, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.21143