Neurons contact each other mostly by synaptic transmission at synapses. The maintenance of synaptic transmission relies on vesicle endocytosis, which recycles fused vesicles for the second round of exocytosis. My goal is to improve our understanding on the cellular and molecular mechanisms underlying synaptic vesicle endocytosis, which are the building block for the maintenance of synaptic transmission and thus the signaling process of the nervous system. Our progress in the last year is described below. Vesicle exocytosis is catalyzed by the SNARE complex, composed of synaptobrevin at the vesicle membrane and SNAP25 and syntaxin at the plasma membrane (Sudhof, 2004;Jackson and Chapman, 2008). After exocytosis, endocytosis retrieves fused vesicle membrane and proteins. The most common form of endocytosis is slow endocytosis, which occurs over tens of seconds. Slow endocytosis involves many classical endocytic proteins, such as dynamin, clathrin, AP2, and auxilin, which are different from the SNARE proteins (Dittman and Ryan, 2009). Owing to the overwhelming role of SNARE proteins in exocytosis and a seemingly clear difference between exo- and endocytic protein machineries, few studies have examined the role of SNARE proteins in endocytosis. whether SNARE proteins are involved in endocytosis is large unclear. We addressed this question at two synapses, the cultured hippocampal synapse and the large calyx of Held synapse. At the cultured hippocampal synapse, we knocked down two SNARE proteins, synaptobrevin and SNAP25. We found that these two proteins are involved in slow classical endocytosis at hippocampal synapses. At the calyx of Held synapse where both rapid and slow endocytosis can be recorded, we found that all three SNARE proteins are involved in both rapid and slow endocytosis. Taken together, these results suggest a critical role for all three SNARE proteins in both exo- and endocytosis. This shared mechanism, the dual role of three SNARE proteins in exo- and endocytosis, may be the molecular substrate underlying the tight exo- and endocytosis coupling, a phenomenon critical for the maintenance of exocytosis at secretory cells, including synapses.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$1,528,330
Indirect Cost
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Park, Soonhong; Ahuja, Malini; Kim, Min Seuk et al. (2016) Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV. EMBO Rep 17:266-78
Wen, Peter J; Grenklo, Staffan; Arpino, Gianvito et al. (2016) Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane. Nat Commun 7:12604
Xu, Jianhua; Wu, Xin-Sheng; Sheng, Jiansong et al. (2016) α-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals. J Neurosci 36:4408-14
Baydyuk, Maryna; Xu, Jianhua; Wu, Ling-Gang (2016) The calyx of Held in the auditory system: Structure, function, and development. Hear Res 338:22-31
Zhao, Wei-Dong; Hamid, Edaeni; Shin, Wonchul et al. (2016) Hemi-fused structure mediates and controls fusion and fission in live cells. Nature 534:548-52
Baydyuk, Maryna; Wu, Xin-Sheng; He, Liming et al. (2015) Brain-derived neurotrophic factor inhibits calcium channel activation, exocytosis, and endocytosis at a central nerve terminal. J Neurosci 35:4676-82
Peng, Shiyong; Xu, Jianhua; Pelkey, Kenneth A et al. (2015) Suppression of agrin-22 production and synaptic dysfunction in Cln1 (-/-) mice. Ann Clin Transl Neurol 2:1085-104
Wu, Ling-Gang; Hamid, Edaeni; Shin, Wonchul et al. (2014) Exocytosis and endocytosis: modes, functions, and coupling mechanisms. Annu Rev Physiol 76:301-31
Wu, Xin-Sheng; Zhang, Zhen; Zhao, Wei-Dong et al. (2014) Calcineurin is universally involved in vesicle endocytosis at neuronal and nonneuronal secretory cells. Cell Rep 7:982-8
Wu, Xin-Sheng; Wu, Ling-Gang (2014) The yin and yang of calcium effects on synaptic vesicle endocytosis. J Neurosci 34:2652-9

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