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

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.

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.

CALCIUM channels regulation; VOLTAGE-gated ion channels; PROTEOLYSIS; CELL membranes; NEURAL physiology

eLife, 2016, p1

2050-084X

Academic Journal

10.7554/eLife.21143