A positive feedback loop between Flower and PI(4,5)P2 at periactive zones controls bulk endocytosis in Drosophila
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 Ca2+ channel-dependent phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) compartmentalization governs control of these processes in Drosophila. Strong stimuli trigger PI(4,5)P2 microdomain formation at periactive zones. Upon exocytosis, Flower translocates from SVs to periactive zones, where it increases PI(4,5)P2 levels via Ca2+ influxes. Remarkably, PI(4,5)P2 directly enhances Flower channel activity, thereby establishing a positive feedback loop for PI(4,5)P2 microdomain compartmentalization. PI(4,5)P2 microdomains drive ADBE and SV reformation from bulk endosomes. PI(4,5)P2 further retrieves Flower to bulk endosomes, terminating endocytosis. We propose that the interplay between Flower and PI(4,5)P2 is the crucial spatiotemporal cue that couples exocytosis to ADBE and subsequent SV reformation.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided.
Article and author information
Ministry of Science and Technology, Taiwan (107-2311-B-001-003-MY3)
- Chi-Kuang Yao
Ministry of Science and Technology, Taiwan (106-0210-01-15-02)
- Chi-Kuang Yao
Ministry of Science and Technology, Taiwan (107-0210-01-19-01)
- Chi-Kuang Yao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Hugo J Bellen, Baylor College of Medicine, United States
- Received: June 17, 2020
- Accepted: December 9, 2020
- Accepted Manuscript published: December 10, 2020 (version 1)
- Version of Record published: December 18, 2020 (version 2)
© 2020, Yao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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