Mechanisms of Vesicle Priming and Short-Term Plasticity

囊泡启动和短期可塑性的机制

• 批准号: 7015005
• 负责人: CHRISTIAN ROSENMUND
• 金额: $ 33.87万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7015005
• 关键词: Mechanisms; Vesicle; Priming; Short; Term

DESCRIPTION (provided by applicant): Before Ca 2+ dependent neurotransmitter release from the presynapse can be achieved, vesicle have to traffic to the active zone and prime to a fusion competent state. Vesicle priming is 1 of the key processes determining the efficiency of the synaptic transmission and plasticity. Central to the vesicle priming step is the controlled assembly of the synaptic trimeric SNARE protein complex consisting of Syntaxin 1, SNAP-25 and Synaptobrevin. Syntaxin 1 is the only synaptic SNARE protein that contains a regulatory, putative autoinhibitory domain, and it is thought that the closed, autoinhibitory conformation has to be opened before SNARE assembly can proceed. The putative function of the essential priming factors Munc13-1 and -2 is to catalyze this conformational change. In addition, Munc13 isoforms may dynamically regulate vesicle priming in response to presynaptic activity. Munc13-1 dependent synapses depress during trains of action potential, and Munc13-2 dependent synapses augment. The aims of this proposal is to functionally analyze the role of the conformational switch in Syntaxin 1 by studying synaptic transmission from murine neurons that express a mutation in the endogenous Syntaxin 1 protein locked in the open conformation. Second, we aim to analyze the molecular mechanism of Munc13 function by systematic analysis of the role of Munc13 domains in vesicle priming using a gain of function rescue approach. We will finally analyze how Munc13 isoforms regulate short-term plasticity in individual synapses, and how Munc13 dependent depression and augmentation control information flow and synaptic plasticity in the central nervous system. A molecular description of the the 2 key molecules involved in vesicle priming will aid the design of therapeutic drugs manipulating the efficacy and plasticity of presynaptic function. Moreover, a detailed knowledge of the mechanisms of neurotransmitter release is critical for the understanding of ethnology and treatment of neurological diseases.

描述（由申请人提供）：在Ca 2+依赖性神经递质释放之前，可以实现散发前的神经递质，囊泡必须访问活性区，并将其质量到达融合胜任状态。囊泡启动是确定突触传播和可塑性效率的关键过程中的1。囊泡启动步骤的核心是由索法蛋白1，SNAP-25和Synaptobrevin组成的突触三聚体SNARE蛋白复合物的受控组装。语法1是唯一包含调节性的自身抑制域的突触snare蛋白，并且认为在进行工具组装之前，必须打开封闭的自身抑制构型。基本启动因子munc13-1和-2的推定功能是催化这种构象变化。此外，MUNC13同工型可能会动态调节囊泡启动，以响应突触前活性。 MUNC13-1依赖性突触在动作电位期间降低，Munc13-2依赖的突触增加。该提案的目的是通过研究鼠神经元的突触传递来分析构象开关在语法1中的作用，这些突触传播表达在开放构象中锁定的内源性语法1蛋白中突变。其次，我们旨在通过系统分析Musc13域在囊泡启动中的作用，使用功能救援方法来分析MUNC13功能的分子机制。我们最终将分析MUNC13同工型如何调节单个突触中的短期可塑性，以及中枢神经系统中MUNC13依赖性抑郁和增强控制信息流和突触可塑性。对囊泡启动的两个关键分子的分子描述将有助于设计处理突触前功能的功效和可塑性的治疗药物。此外，对神经递质释放机制的详细知识对于了解民族学和治疗神经系统疾病至关重要。