A novel region in the Cav2.1 α1 subunit C-terminus regulates fast synaptic vesicle fusion and vesicle docking at the mammalian presynaptic active zone

In central nervous system (CNS) synapses, action potential-evoked neurotransmitter release is principally mediated by Ca(v)2.1 calcium channels (Ca(v)2.1) and is highly dependent on the physical distance between Ca(v)2.1 and synaptic vesicles (coupling). Although various active zone proteins are proposed to control coupling and abundance of Ca(v)2.1 through direct interactions with the Ca(v)2.1 al subunit C-terminus at the active zone, the role of these interaction partners is controversial. To define the intrinsic motifs that regulate coupling, we expressed mutant Ca(v)2.1 subunits on a Ca(v)2.1 null background at the calyx of Held presynaptic terminal. Our results identified a region that directly controlled fast synaptic vesicle release and vesicle docking at the active zone independent of Ca(v)2.1 abundance. In addition, proposed individual direct interactions with active zone proteins are insufficient for Ca(v)2.1 abundance and coupling. Therefore, our work advances our molecular understanding of Ca(v)2.1 regulation of neurotransmitter release in mammalian CNS synapses.