Synaptotagmin 1 directs repetitive release by coupling vesicle exocytosis to the Rab3 cycle

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Abstract

In response to Ca²⁺ influx, a synapse needs to release neurotransmitters quickly while immediately preparing for repeat firing. How this harmonization is achieved is not known. Here, we found that the Ca²⁺ sensor synaptotagmin 1 orchestrates the membrane association/disassociation cycle of Rab3, which functions in activity-dependent recruitment of synaptic vesicles. In the absence of Ca²⁺, synaptotagmin 1 binds to Rab3 GTPase activating protein (GAP) and inhibits the GTP hydrolysis of Rab3 protein. Rab3 GAP resides on synaptic vesicles and synaptotagmin 1 is essential for the synaptic localization of Rab3 GAP. In the presence of Ca²⁺, synaptotagmin 1 releases Rab3 GAP and promotes membrane disassociation of Rab3. Without synaptotagmin 1, the tight coupling between vesicle exocytosis and Rab3 membrane disassociation is disrupted. We uncovered the long-sought molecular apparatus linking vesicle exocytosis to Rab3 cycling and we also revealed the important function of synaptotagmin 1 in repetitive synaptic vesicle release.

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Yunsheng Cheng

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Jiaming Wang

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Yu Wang

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Mei Ding

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

For correspondence
mding@genetics.ac.cn

Competing interests
The authors declare that no competing interests exist.

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