Proteolytic maturation of α 2 δ controls the probability of synaptic vesicular release.

Auxiliary α2 δ subunits are important proteins for trafficking of voltage-gated calcium channels (CaV ) at the active zones of synapses. We have previously shown that the post-translational proteolytic cleavage of α2 δ is essential for their modulatory effects on the trafficking of N-type (CaV 2.2) calcium channels (Kadurin et al., 2016). We extend these results here by showing that the probability of presynaptic vesicular release is reduced when an uncleaved α2 δ is expressed in rat neurons and that this inhibitory effect is reversed when cleavage of α2 δ is restored. We also show that asynchronous release is influenced by the maturation of α2 δ-1, highlighting the role of CaV channels in this component of vesicular release. We present additional evidence that CaV 2.2 co-immunoprecipitates preferentially with cleaved wild-type α2 δ. Our data indicate that the proteolytic maturation increases the association of α2 δ-1 with CaV channel complex and is essential for its function on synaptic release.