Secretagogin regulates asynchronous and spontaneous glutamate release in hippocampal neurons through interaction with Doc2α.

Synaptic vesicle (SV) exocytosis is orchestrated by protein machineries consisting of the SNARE complex, Ca sensors, and their partners. Secretagogin (SCGN) is a Ca-binding protein involved in multiple forms of vesicle secretion. Although SCGN is implicated in multiple neurological disorders, its role in SV exocytosis in neurons remains unknown. Here, using knockout and knockdown techniques, we report that SCGN could regulate the asynchronous and spontaneous forms of excitatory but not inhibitory SV exocytosis in mouse hippocampal neurons. Furthermore, SCGN functioned in glutamate release via directly interacting with Doc2α, a high-affinity Ca sensor specific for asynchronous and spontaneous SV exocytosis. Conversely, the interaction with SCGN is also required for Doc2α to execute its Ca sensor function in SV release. Together, our study revealed that SCGN plays an important role in asynchronous and spontaneous glutamate release through its interaction with Doc2α.