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Synaptic vesicle (SV) endocytosis is coupled to exocytosis to maintain SV pool size and thus neurotransmitter release. Intense stimulation induces activity-dependent bulk endocytosis (ADBE) to recapture large quantities of SV constituents in large endosomes from which SVs reform. How these consecutive processes are spatiotemporally coordinated remains unknown. Here, we show that Flower Ca 2+  channel-dependent phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) compartmentalization governs control of these processes in  Drosophila . Strong stimuli trigger PI(4,5)P 2  microdomain formation at periactive zones. Upon exocytosis, Flower translocates from SVs to periactive zones, where it increases PI(4,5)P 2  levels via Ca 2+  influxes. Remarkably, PI(4,5)P 2  directly enhances Flower channel activity, thereby establishing a positive feedback loop for PI(4,5)P 2  microdomain compartmentalization. PI(4,5)P 2  microdomains drive ADBE and SV reformation from bulk endosomes. PI(4,5)P 2  further retrieves Flower to bulk endosomes, terminating endocytosis. We propose that the interplay between Flower and PI(4,5)P 2  is the crucial spatiotemporal cue that couples exocytosis to ADBE and subsequent SV reformation.

A positive feedback loop between Flower and PI(4,5)P 2 at periactive zones controls bulk endocytosis in Drosophila