A Synaptic Vesicle-Associated Ca²⁺ Channel Promotes Endocytosis and Couples Exocytosis to Endocytosis

Synaptic vesicle (SV) exo- and endocytosis are tightly coupled to sustain neurotransmission in presynaptic terminals, and both are regulated by Ca²⁺. Ca²⁺ influx triggered by voltage-gated Ca²⁺ channels is necessary for SV fusion. However, extracellular Ca²⁺ has also been shown to be required for endocytosis. The intracellular Ca²⁺ levels (<1 μM) that trigger endocytosis are typically much lower than those (>10 μM) needed to induce exocytosis, and endocytosis is inhibited when the Ca²⁺ level exceeds 1 μM. Here, we identify and characterize a transmembrane protein associated with SVs that, upon SV fusion, localizes at periactive zones. Loss of Flower results in impaired intracellular resting Ca²⁺ levels and impaired endocytosis. Flower multimerizes and is able to form a channel to control Ca²⁺ influx. We propose that Flower functions as a Ca²⁺ channel to regulate synaptic endocytosis and hence couples exo- with endocytosis.