G protein-mediated modulation of synaptic vesicle fusion

G 蛋白介导的突触小泡融合调节

基本信息

批准号：
7414785
负责人：
SIMON T ALFORD
金额：
$ 36.93万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-19 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7414785
关键词：
AMPA Receptors Accounting Affect Affinity Binding Brain Cleaved cell Complex Data Depressed mood Dyes Ecology End Point Endocytosis Event Exocytosis Extracellular Space Fluorescence G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors GTP-Binding Proteins Glutamates Hippocampus (Brain)Imaging Techniques Individual Investigation Kinetics Label Lampreys Laser Scanning Confocal Microscopy Location Measures Mediating Membrane Mental Depression Methods Modeling Modification Molecular Target Monitor N-Methyl-D-Aspartate Receptors Nervous system structure Neuronal Plasticity Neurons Neurotransmitters Outcome Permeability Preparation Presynaptic Receptors Presynaptic Terminals Probability Property Rate Receptor Activation Recycling Relative (related person)Research Personnel SNAP receptor Serotonin Signal Transduction Pathway Slice Speed Spinal Cord Structure Synapses Synaptic Cleft Synaptic Transmission Synaptic Vesicles System Techniques Time Tissues Vesicle Water Work effusion lipid solubility neurotransmission neurotransmitter release novel postsynaptic presynaptic programs quantum receptor response serotonin receptor size transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Modulation of the efficacy of synaptic transmission is a key component of neural plasticity, which is, in turn, a defining feature of the brain. Receptors located on the presynaptic terminal are known to profoundly depress neurotransmitter release. Of these, G protein-coupled receptors are ubiquitous. We have demonstrated that G protein-coupled receptors inhibit synaptic transmission by an effect mediated directly at the core complex for vesicle fusion. Gbg binds directly to SNAP-25 incorporated into the SNARE complex of primed vesicles. We now hypothesize that the mechanism for this modulation is an alteration in fusion pore dynamics as the synaptic vesicle releases transmitter into the synaptic cleft. This change in mode of transmission is likely to have profound consequences both to the way synaptic transmission actually works, and to the way we interpret it as working. Transient fusion, will conserve vesicles during repetitive activity, it may also change the mode of synaptic transmission by favoring different postsynaptic receptors with different affinities and different subsynaptic locations. In this proposal we seek to determine the mechanism by which presynaptic G protein-coupled receptors modulate release of neurotransmitter. We will quantify the duration of incomplete vesicle fusion events from the presynaptic terminal caused by presynaptic G proteins using styryl dye labeling of fusing synaptic vesicles? We also wish to determine the affects of presynaptic receptor activation on the timecourse and concentration of neurotransmitter in the synaptic cleft by measuring and modeling the kinetics of postsynaptic receptor activation. We will also determine the effects that altering these parameters will impose on the relative activation of different postsynaptic ionotropic receptors. Finally, we will investigate the affect of presynaptic G proteins on the properties of individual synaptic contacts using high-speed imaging techniques.

描述（由申请人提供）：突触传递功效的调节是神经可塑性的关键组成部分，而神经可塑性又是大脑的一个决定性特征。众所周知，位于突触前末端的受体可以极大地抑制神经递质的释放。其中，G 蛋白偶联受体无处不在。我们已经证明，G 蛋白偶联受体通过直接在囊泡融合核心复合物介导的作用来抑制突触传递。 Gbg 直接与掺入引发的囊泡的 SNARE 复合物中的 SNAP-25 结合。我们现在假设这种调节的机制是当突触小泡将递质释放到突触间隙时融合孔动力学的改变。这种传递方式的变化可能会对突触传递的实际工作方式以及我们解释其工作的方式产生深远的影响。瞬时融合将在重复活动期间保留囊泡，它还可能通过有利于具有不同亲和力和不同突触下位置的不同突触后受体来改变突触传递模式。在本提案中，我们试图确定突触前 G 蛋白偶联受体调节神经递质释放的机制。我们将使用融合突触小泡的苯乙烯基染料标记来量化由突触前 G 蛋白引起的突触前末端不完全囊泡融合事件的持续时间？我们还希望通过测量和模拟突触后受体激活的动力学来确定突触前受体激活对突触间隙神经递质浓度的影响。我们还将确定改变这些参数对不同突触后离子型受体的相对激活的影响。最后，我们将使用高速成像技术研究突触前 G 蛋白对单个突触接触特性的影响。