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.

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Wu, Ling-Gang; Hamid, Edaeni; Shin, Wonchul et al. (2014) Exocytosis and endocytosis: modes, functions, and coupling mechanisms. Annu Rev Physiol 76:301-31
Chiang, Hsueh-Cheng; Shin, Wonchul; Zhao, Wei-Dong et al. (2014) Post-fusion structural changes and their roles in exocytosis and endocytosis of dense-core vesicles. Nat Commun 5:3356
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
Xu, Jianhua; Luo, Fujun; Zhang, Zhen et al. (2013) SNARE proteins synaptobrevin, SNAP-25, and syntaxin are involved in rapid and slow endocytosis at synapses. Cell Rep 3:1414-21
Zhang, Zhen; Wang, Dongsheng; Sun, Tao et al. (2013) The SNARE proteins SNAP25 and synaptobrevin are involved in endocytosis at hippocampal synapses. J Neurosci 33:9169-75
Wu, Xin-Sheng; McNeil, Benjamin D; Xu, Jianhua et al. (2009) Ca(2+) and calmodulin initiate all forms of endocytosis during depolarization at a nerve terminal. Nat Neurosci 12:1003-10
Wu, Xin-Sheng; Wu, Ling-Gang (2009) Rapid endocytosis does not recycle vesicles within the readily releasable pool. J Neurosci 29:11038-42