Munc13-1通过与syntaxin-1相互作用促进神经递质快速释放的分子机制研究

理解囊泡分泌的调控过程是神经生物学最基本，最重要的问题之一。信号的快速传导是神经系统正常工作的基本要求，受多种蛋白精确调控的SNARE复合体介导的囊泡融合是已知实现信号快速传导的主要途径。Munc13-1是参与调节囊泡快速融合的重要蛋白，缺失该蛋白会对神经递质释放产生严重影响，但由于Munc13-1结构的复杂性，其调控突触囊泡融合的分子机制目前还不清楚。为了阐明Munc13-1调控囊泡快速融合的分子机制，本课题通过前期体内、体外实验，初步确定了Munc13-1作用的靶点分子是syntaxin-1，并锁定syntaxin-1的linker区域为相互作用区域，将继续探寻linker区域中与Munc13-1作用的具体位点。通过本课题的研究，将首次阐明Munc13-1通过与syntaxin-1相互作用促进神经递质快速释放的分子机制，加深对神经信号传导机制的理解，为研究神经疾病发病机制提供理论依据。

Understanding the regulation of vesicle release is one of most fundamental questions in neuroscience research. Signal has to be transferred rapidly in normal nerve system. SNARE complex mediated vesicle fusion, which is precisely regulated by many proteins, is the known major route for signal transduction. Munc13-1, as known as an important regulator for fast vesicle fusion, severely impairs neurotransmitter release with its deficiency. Because of the complexity of its structure, the molecular mechanisms of Munc13-1 in regulating rapid synaptic vesicle fusion largely remain unclear. To discover the underlying mechanisms of Munc13-1 in fast vesicle fusion, we perform a set of experiments both in vivo and in vitro. Our preliminary results identify syntaxin-1 as the functional target of Munc13-1, and narrow down the linker region of syntaxin-1 as responsible sequence for their interaction. Further discovering key Munc13-1 interacting residues in syntaxin-1 linker region will be done in this project. With this study, we are going to clarify the mechanisms of Munc13-1 in facilitating fast neurotransmitter release via interacting with syntaxin-1 for the first time. The mechanisms of signal transduction will be gone deeper and more evidence will be uncovered in the pathogenesis of neuronal diseases.