The Role of Cysteine String Protein for Fast Neurotransmitter Release

调节神经递质分泌介导神经系统神经细胞之间的交流。“发送者”细胞利用储存在突触囊泡中的神经递质将其电信号编码为化学信号。神经递质被分泌到“接收器”细胞中，接收器将信号解码回电信号。神经递质的分泌是通过囊泡膜与细胞膜融合排出其内容物来完成的。我们对驱动囊泡融合的分子机制知之甚少。本文的目标是研究这些分子机制，特别是半胱氨酸-弦蛋白（CSP）的作用。该项目将验证CSP可能通过调节Ca2+通道、Ca2+通道-囊泡连接和/或囊泡融合来调节分泌的假设。这将通过采用果蝇的基因操纵运动神经末梢作为模型系统来实现。神经细胞异常快速和精确的交流是理解神经系统如何工作的核心——我们如何感知、移动、感觉、学习和记忆。分泌衰竭对人的生命有致命的影响。在大多数情况下，异常是如此严重，胚胎发育将无法继续。即使是神经递质分泌的细微缺陷也会严重损害大脑的高级功能，如学习和记忆。CSP最近被认为是治疗人类躁狂抑郁症的一个重要因素。因此，正在进行的研究对我们关于神经元分泌的基本知识以及随后对人类医学检测、治疗和可能预防神经系统疾病具有至关重要的意义。

Regulated neurotransmitter secretion mediates communication between nerve cells of the nervous system. A "sender" cell encodes its electrical signal into a chemical signal by using a neurotransmitter stored in synaptic vesicles. The neurotransmitter is secreted onto a "receiver" cell, which decodes the signal back into an electrical signal. Neurotransmitter secretion is accomplished by fusing the vesicle membrane with the cell membrane expelling its content. Little is known about the molecular machinery driving vesicle fusion. The goal of this proposal is to investigate these molecular mechanisms and, in particular, the role of cysteine-string protein (CSP). This project will test the hypothesis that CSP may mediate secretion by modulating Ca2+ channels, Ca2+ channel-vesicle linkage, and/or vesicle fusion. This will be achieved by employing genetically manipulated motor nerve terminals of the fruit fly Drosophila as a model system.The extraordinary fast and precise communication of nerve cells is central to understand how the nervous system works - how we perceive, move, feel, learn, and remember. Failure of secretion has a fatal influence on human life. In most cases, the abnormalities are so severe that embryonic development will not proceed. Even subtle defects of neurotransmitter secretion severely impair higher brain functions like learning and memory. CSP has been recently implicated as an important factor during the treatment of manic depression in humans. Thus, the research being conducted has crucial implications on our basic knowledge of neuronal secretion and subsequently on human medicine to detect, to treat, and to possibly prevent neurological disorders.