Action potentials, when arriving at presynaptic terminals, elicit Ca 2+ influx through voltage-gated Ca 2+ channels. Intracellular [Ca 2+] elevation around the channels subsequently triggers synaptic vesicle exocytosis and also induces various protein reactions that regulate vesicle endocytosis and recycling to provide for long-term sustainability of synaptic transmission. Recent studies using membrane capacitance measurements, as well as high-resolution optical imaging, have revealed that the dominant type of synaptic vesicle endocytosis at central nervous system synapses is mediated by clathrin and dynamin. Furthermore, Ca 2+-dependent mechanisms regulating endocytosis may operate in different ways depending on the distance from Ca 2+ channels: (1) intracellular Ca 2+ in the immediate vicinity of a Ca 2+ channel plays an essential role in triggering endocytosis, and (2) intracellular Ca 2+ traveling far from the channels has a modulatory effect on endocytosis at the periactive zone. Here, I integrate the latest progress in this field to propose a compartmental model for regulation of vesicle endocytosis at synapses and discuss the possible roles of presynaptic Ca 2+-binding proteins including calmodulin, calcineurin and synaptotagmin.
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