Mechanisms of Vesicle Priming and Short-Term Plasticity

囊泡启动和短期可塑性的机制

• 批准号: 7393076
• 负责人: CHRISTIAN ROSENMUND
• 金额: $ 32.89万
• 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/7393076
• 关键词: Action Potentials; Affect; Area; Back; Binding; Brain; Cell membrane; Characteristics; Chromosome Pairing; Classification; Complex; Computer information processing; Consumption; Depressed mood; Endocrine System Process; Ethnology; Event; Exocytosis; Functional disorder; Future; Helix (Snails); Image; Individual; Kinetics; Knock-out; Knowledge; Lead; Mediating; Mental Depression; Modeling; Molecular; Molecular Conformation; Mus; Mutation; Mutation Analysis; Neuraxis; Neurons; Output; Pharmaceutical Preparations; Physiology; Population; Process; Property; Protein Isoforms; Proteins; Rate; Regulation; Role; SNAP receptor; Signal Transduction; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Therapeutic; Thinking; Training; Transgenic Mice; Translating; VAMP-2; Vesicle; design; ear helix; gain of function; in vivo; mutant; nervous system disorder; neurotransmitter release; presynaptic; prevent; research study; response; syntaxin; syntaxin 1; syntaxin 1A; syntaxin 1B; trafficking; vesicle-associated membrane protein

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）：在实现突触前释放 Ca 2+ 依赖性神经递质之前，囊泡必须运输至活性区并准备进入融合能力状态。囊泡启动是决定突触传递效率和可塑性的关键过程之一。囊泡启动步骤的核心是由 Syntaxin 1、SNAP-25 和 Synaptobrevin 组成的突触三聚 SNARE 蛋白复合物的受控组装。突触融合蛋白 1 是唯一含有调节性、假定的自抑制结构域的突触 SNARE 蛋白，人们认为，在 SNARE 组装进行之前，必须打开封闭的自抑制构象。基本启动因子 Munc13-1 和 -2 的假定功能是催化这种构象变化。此外，Munc13 亚型可以动态调节囊泡启动以响应突触前活动。 Munc13-1 依赖性突触在动作电位序列期间抑制，而 Munc13-2 依赖性突触增强。该提案的目的是通过研究表达锁定在开放构象的内源 Syntaxin 1 蛋白突变的小鼠神经元的突触传递，从功能上分析 Syntaxin 1 构象开关的作用。其次，我们的目标是通过使用功能获得拯救方法系统分析 Munc13 结构域在囊泡启动中的作用，来分析 Munc13 功能的分子机制。最后，我们将分析 Munc13 异构体如何调节个体突触的短期可塑性，以及 Munc13 依赖性抑制和增强如何控制中枢神经系统的信息流和突触可塑性。对参与囊泡启动的两个关键分子的分子描述将有助于设计控制突触前功能的功效和可塑性的治疗药物。此外，详细了解神经递质释放机制对于理解人种学和神经系统疾病的治疗至关重要。