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.

pOpsicle: An all-optical reporter system for synaptic vesicle recycling combining pH-sensitive fluorescent proteins with optogenetic manipulation of neuronal activity

“…snt-1(md290) mutants displayed more severe recycling defects after strong stimulation, indicating that it is dispensable for recycling at lower activity. This is in stark contrast to previous results in mammalian hippocampal neurons in which synaptotagmin-1 promotes slow small-scale endocytosis, while inhibiting bulk retrieval during sustained neurotransmission (Chen et al, 2022). Although a role of SNT-1 in the slow clathrin-mediated endocytosis is likely also in C. elegans and simply not efficiently reported by pOpsicle, a role in inhibition of bulk endocytosis might not be conserved between nematodes and mammals.…”

pOpsicle: An all-optical reporter system for synaptic vesicle recycling combining pH-sensitive fluorescent proteins with optogenetic manipulation of neuronal activity

“…snt-1(md290) mutants displayed more severe recycling defects after strong stimulation, indicating that it is dispensable for recycling at lower activity. This is in stark contrast to previous results in mammalian hippocampal neurons in which synaptotagmin promotes slow small-scale endocytosis, while inhibiting bulk retrieval during sustained neurotransmission (Chen et al, 2022). Although a role of SNT-1 in the slow clathrin-mediated endocytosis is likely also in C. elegans and simply not efficiently reported by pOpsicle, a role in inhibition of bulk endocytosis might not be conserved between nematodes and mammals.…”

SYT1-Associated Neurodevelopmental Disorder: A Narrative Review

“…The efficiency of endocytosis and exocytosis is crucial to establishing efficient neuronal transmission. SYT1 helps to establish this via a bidirectional Ca 2+ sensing capability that links endocytosis and exocytosis [ 35 ]. Previous labs have recognized that SYT1 is able to initiate slow and small clathrin mediated endocytosis (CME) and/or block bulk-sized endocytosis during increased neural activity [ 35 ].…”

“…SYT1 helps to establish this via a bidirectional Ca 2+ sensing capability that links endocytosis and exocytosis [ 35 ]. Previous labs have recognized that SYT1 is able to initiate slow and small clathrin mediated endocytosis (CME) and/or block bulk-sized endocytosis during increased neural activity [ 35 ]. In contrast to the pivotal role of C2B in exocytosis, it has been demonstrated that either C2B or C2A can be involved in SYT1-mediated endocytosis [ 1 ].…”

“…However, Ca 2+ binding to either the C2A or C2B domain is necessary in the acceleration of endocytosis [ 1 ]. Experiments have shown that mutations in either C2A or C2B (but not in both simultaneously) rescued knockdown-decrease in transferrin uptake, which represented CME and further established the redundancy of C2AB in endocytosis [ 35 ]. It was further demonstrated that C2B is needed for bulk endocytosis [ 35 ].…”