期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 36, 页码 8797-8815出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0338-17.2017
关键词
C. elegans; exocytosis; membrane fusion; Munc18; SNARE; synapse
资金
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2015-06438, 2014-06471, RGPIN-2016-04574]
- Heart and Stroke Foundation of Ontario [0171]
- Canadian Institute of Health Research [MOP-93665, 130573, MOP-93619, 123250]
- NIH [R35 NS097333, NS037200, NS049044]
- National Natural Science Foundation of China [31671052]
- Junior Thousand Talents Program of China
- Wuhan Morning Light Plan of Youth Science and Technology [2017050304010295]
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- Parkinson's UK [K-1405] Funding Source: researchfish
Munc18-1/UNC-18 is believed to prime SNARE-mediated membrane fusion, yet the underlying mechanisms remain enigmatic. Here, we examine how potential gain-of-function mutations of Munc18-1/UNC-18 affect locomotory behavior and synaptic transmission, and how Munc18-1-mediated priming is related to Munc13-1/UNC-13 and Tomosyn/TOM-1, positive and negative SNARE regulators, respectively. We show that a Munc18-1(P335A)/UNC-18(P334A) mutation leads to significantly increased locomotory activity and acetylcholine release in Caenorhabditis elegans, as well as enhanced synaptic neurotransmission in cultured mammalian neurons. Importantly, similar to tom-1 null mutants, unc-18(P334A) mutants partially bypass the requirement of UNC-13. Moreover, unc-18( P334A) and tom-1 null mutations confer a strong synergy in suppressing the phenotypes of unc-13 mutants. Through biochemical experiments, we demonstrate that Munc18-1( P335A) exhibits enhanced activity in SNARE complex formation as well as in binding to the preformed SNARE complex, and partially bypasses the Munc13-1 requirement in liposome fusion assays. Our results indicate that Munc18-1/UNC-18 primes vesicle fusion downstream of Munc13-1/UNC-13 by templating SNARE complex assembly and acts antagonistically with Tomosyn/TOM-1.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据