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

The auxiliary α(2)δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α(2) and δ. We now show, using α(2)δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (Ca(V)2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α(2)δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α(2)δ. Uncleaved α(2)δ does not support trafficking of Ca(V)2.2 channel complexes into neuronal processes, and inhibits Ca(2+) entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. We propose a model whereby uncleaved α(2)δ subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of α(2)δ then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes. DOI: http://dx.doi.org/10.7554/eLife.21143.001