Synaptotagmin-1 is a bidirectional Ca2+ sensor for neuronal endocytosis.

Abstract

Exocytosis and endocytosis are tightly coupled. In addition to initiating exocytosis, Ca2+ plays critical roles in exo-endocytosis coupling in neurons and non-neuronal cells. Both positive and negative roles of Ca2+ in endocytosis have been reported, however the Ca2+-inhibition in endocytosis remains debatable with unknown mechanisms. Here we show that synaptotagmin-1 (Syt1), the primary Ca2+ sensor initiating exocytosis, plays bidirectional and opposite roles in exo-endocytosis coupling by promoting the slow small-sized clathrin-mediated endocytosis but inhibiting the fast large-sized bulk endocytosis. The Ca2+-binding ability is required for Syt1 to regulate both types of endocytic pathways, disruption of which leads to inefficient vesicle recycling under mild stimulation but excessive membrane retrieval following intense stimulation. The Ca2+-dependent membrane tubulation may explain the opposite endocytic roles of Syt1 and provide a general membrane-remodeling working model for endocytosis determination. Thus, Syt1 is a primary bidirectional Ca2+ sensor facilitating clathrin-mediated endocytosis but clamping bulk endocytosis, probably by manipulating membrane curvature, to ensure both efficient and precise coupling of endocytosis to exocytosis.