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

Auxiliary α(2)δ subunits are important proteins for trafficking of voltage-gated calcium channels (Ca(V)) at the active zones of synapses. We have previously shown that the post-translational proteolytic cleavage of α(2)δ is essential for their modulatory effects on the trafficking of N-type (Ca(V)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 α(2)δ is expressed in rat neurons and that this inhibitory effect is reversed when cleavage of α(2)δ is restored. We also show that asynchronous release is influenced by the maturation of α(2)δ−1, highlighting the role of Ca(V) channels in this component of vesicular release. We present additional evidence that Ca(V)2.2 co-immunoprecipitates preferentially with cleaved wild-type α(2)δ. Our data indicate that the proteolytic maturation increases the association of α(2)δ−1 with Ca(V) channel complex and is essential for its function on synaptic release.