Synaptotagmin-1 is a bidirectional Ca 2+ sensor for neuronal endocytosis

Abstract

Significance Precise and efficient coupling of endocytosis to exocytosis is critical for neurotransmission. The activity-dependent facilitation of endocytosis has been well established for efficient membrane retrieval; however, whether neural activity clamps endocytosis to avoid excessive membrane retrieval remains debatable with the mechanisms largely unknown. The present work provides compelling evidence that synaptotagmin-1 (Syt1) functions as a primary bidirectional Ca 2+ sensor to promote slow, small-sized clathrin-mediated endocytosis but inhibit the fast, large-sized bulk endocytosis during elevated neural activity, the disruption of which leads to inefficient vesicle recycling under mild stimulation but excessive membrane retrieval following sustained neurotransmission. Thus, Syt1 serves as a fine-tuning Ca 2+ sensor to ensure both efficient and precise coupling of endocytosis to exocytosis in response to different neural activities.