Synaptic vesicle (SV) release, recycling, and plastic changes of release probability co-occur side by side within nerve terminals and rely on local Ca²⁺ signals with different temporal and spatial profiles. The mechanisms that guarantee separate regulation of these vital presynaptic functions during action potential (AP)-triggered presynaptic Ca²⁺ entry remain unclear. Combining Drosophila genetics with electrophysiology and imaging reveals the localization of two different voltage-gated calcium channels at the presynaptic terminals of glutamatergic neuromuscular synapses (the Drosophila Ca_v2 homolog, Dmca1A or cacophony, and the Ca_v1 homolog, Dmca1D) but with spatial and functional separation. Ca_v2 within active zones is required for AP-triggered neurotransmitter release. By contrast, Ca_v1 localizes predominantly around active zones and contributes substantially to AP-evoked Ca²⁺ influx but has a small impact on release. Instead, L-type calcium currents through Ca_v1 fine-tune short-term plasticity and facilitate SV recycling. Separate control of SV exo- and endocytosis by AP-triggered presynaptic Ca²⁺ influx through different channels demands efficient measures to protect the neurotransmitter release machinery against Ca_v1-mediated Ca²⁺ influx. We show that the plasma membrane Ca²⁺ ATPase (PMCA) resides in between active zones and isolates Ca_v2-triggered release from Ca_v1-mediated dynamic regulation of recycling and short-term plasticity, two processes which Ca_v2 may also contribute to. As L-type Ca_v1 channels also localize next to PQ-type Ca_v2 channels within axon terminals of some central mammalian synapses, we propose that Ca_v2, Ca_v1, and PMCA act as a conserved functional triad that enables separate control of SV release and recycling rates in presynaptic terminals.

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