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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 α1 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 α 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.