Proteolytic maturation of α₂δ controls the probability of synaptic vesicular release

Auxiliary α₂δ 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 α₂δ is essential for their modulatory effects on the trafficking of N-type (Ca_V2.2) 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 α₂δ is expressed in rat neurons and that this inhibitory effect is reversed when cleavage of α₂δ is restored. We also show that asynchronous release is influenced by the maturation of α₂δ-1, highlighting the role of Ca_V channels in this component of vesicular release. We present additional evidence that Ca_V2.2 co-immunoprecipitates preferentially with cleaved wild-type α₂δ. Our data indicate that the proteolytic maturation increases the association of α₂δ-1 with Ca_V channel complex and is essential for its function on synaptic release.