Synaptotagmin 7 functions as a Ca2+-sensor for synaptic vesicle replenishment

Synaptotagmin (syt) 7 is one of three syt isoforms found in all metazoans; it is ubiquitously expressed, yet its function in neurons remains obscure. Here, we resolved Ca2+ - dependent and Ca2+ - independent synaptic vesicle (SV) replenishment pathways, and found that syt 7 plays a selective and critical role in the Ca2+ - dependent pathway. Mutations that disrupt Ca2+ binding to syt 7 abolish this function, suggesting that syt 7 functions as a Ca2+ - sensor for replenishment. The Ca2+ - binding protein calmodulin (CaM) has also been implicated in SV replenishment, and we found that loss of syt 7 was phenocopied by a CaM antagonist. Moreover, we discovered that syt 7 binds to CaM in a highly specific and Ca2+ - dependent manner; this interaction requires intact Ca2+ - binding sites within syt 7. Together, these data indicate that a complex of two conserved Ca2+ - binding proteins, syt 7 and CaM, serve as a key regulator of SV replenishment in presynaptic nerve terminals.