期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：28
DOI：10.1073/pnas.2106621118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Synaptic vesicle (SV) release from presynaptic terminals requires nanometer precise control of action potential (AP)–triggered calcium influx through voltage-gated calcium channels (VGCCs). SV recycling also depends on calcium signals, though in different spatiotemporal domains. Mechanisms for separate control of SV release and recycling by AP-triggered calcium influx remain elusive. Here, we demonstrate largely independent regulation of release and recycling by two different populations of VGCCs (Ca
v2, Ca
v1), identify Ca
v1 as one of potentially multiple calcium entry routes for endocytosis regulation, and show functional separation of simultaneous calcium signals in the nanometer space of a presynaptic terminal by the plasma membrane calcium ATPase (PMCA). The Ca
v2/Ca
v1/PMCA functional triad may provide conserved means for independent control of different vital presynaptic functions.
Synaptic vesicle (SV) release, recycling, and plastic changes of release probability co-occur side by side within nerve terminals and rely on local Ca
2+ signals with different temporal and spatial profiles. The mechanisms that guarantee separate regulation of these vital presynaptic functions during action potential (AP)–triggered presynaptic Ca
2+ 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 Ca
2+ 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 Ca
2+ influx through different channels demands efficient measures to protect the neurotransmitter release machinery against Ca
v1-mediated Ca
2+ influx. We show that the plasma membrane Ca
2+ 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.
