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

The auxiliary α2 δ 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 α2 δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV 2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α2 δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α2 δ. Uncleaved α2 δ does not support trafficking of CaV 2.2 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 α2 δ subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of α2 δ then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes.