Departments of Biophysics, Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390.
Protein Sci. 2018 Aug;27(8):1364-1391. doi: 10.1002/pro.3445. Epub 2018 Jul 10.
Research for three decades and major recent advances have provided crucial insights into how neurotransmitters are released by Ca -triggered synaptic vesicle exocytosis, leading to reconstitution of basic steps that underlie Ca -dependent membrane fusion and yielding a model that assigns defined functions for central components of the release machinery. The soluble N-ethyl maleimide sensitive factor attachment protein receptors (SNAREs) syntaxin-1, SNAP-25, and synaptobrevin-2 form a tight SNARE complex that brings the vesicle and plasma membranes together and is key for membrane fusion. N-ethyl maleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs) disassemble the SNARE complex to recycle the SNAREs for another round of fusion. Munc18-1 and Munc13-1 orchestrate SNARE complex formation in an NSF-SNAP-resistant manner by a mechanism whereby Munc18-1 binds to synaptobrevin and to a self-inhibited "closed" conformation of syntaxin-1, thus forming a template to assemble the SNARE complex, and Munc13-1 facilitates assembly by bridging the vesicle and plasma membranes and catalyzing opening of syntaxin-1. Synaptotagmin-1 functions as the major Ca sensor that triggers release by binding to membrane phospholipids and to the SNAREs, in a tight interplay with complexins that accelerates membrane fusion. Many of these proteins act as both inhibitors and activators of exocytosis, which is critical for the exquisite regulation of neurotransmitter release. It is still unclear how the actions of these various proteins and multiple other components that control release are integrated and, in particular, how they induce membrane fusion, but it can be expected that these fundamental questions can be answered in the near future, building on the extensive knowledge already available.
三十年的研究和最近的重大进展为钙触发突触小泡胞吐作用中神经递质的释放提供了关键的见解，导致了基础步骤的重建，这些步骤是钙依赖性膜融合的基础，并产生了一个模型，为释放机制的核心组件赋予了明确的功能。可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNAREs）突触融合蛋白 1、SNAP-25 和突触小泡蛋白 2 形成一个紧密的 SNARE 复合物，将囊泡和质膜结合在一起，是膜融合的关键。N-乙基马来酰亚胺敏感因子（NSF）和可溶性 NSF 附着蛋白（SNAPs）通过一种机制将 SNARE 复合物拆开，使 SNARE 重新用于下一轮融合。Munc18-1 和 Munc13-1 通过一种机制以 NSF-SNAP 抗性的方式协调 SNARE 复合物的形成，其中 Munc18-1 与突触小泡蛋白结合，与突触融合蛋白 1 的自我抑制的“封闭”构象结合，从而形成一个组装 SNARE 复合物的模板，Munc13-1 通过桥接囊泡和质膜并催化突触融合蛋白 1 的开放来促进组装。突触融合蛋白 1 作为主要的 Ca 传感器，通过与膜磷脂和 SNARE 结合来触发释放，与复合物相互作用，加速膜融合。许多这些蛋白作为胞吐作用的抑制剂和激活剂起作用，这对于神经递质释放的精确调节至关重要。目前尚不清楚这些各种蛋白和控制释放的其他多个组件的作用是如何整合的，特别是它们如何诱导膜融合，但可以预期，在已经获得的广泛知识的基础上，这些基本问题将在不久的将来得到回答。
