G protein-mediated modulation of synaptic vesicle fusion

G 蛋白介导的突触小泡融合调节

• 批准号: 7248746
• 负责人: SIMON T ALFORD
• 金额: $ 38.58万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 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/7248746
• 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

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，这反过来又是大脑的定义特征。众所周知，位于突触前末端的受体会严重降低神经递质的释放。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核心络合物中介导的囊泡融合的效果抑制突触传播。 GBG直接与液压囊泡的snare复合物掺入的SNAP-25结合。现在，我们假设该调节的机制是融合孔动力学的改变，因为突触囊泡释放到突触裂缝中。这种传输方式的这种变化可能会对突触传输实际运作的方式以及我们将其解释为有效的方式产生深远的影响。瞬态融合，将在重复活性期间保存囊泡，它也可能通过偏爱不同亲和力和不同突触后位置的不同突触后受体来改变突触传播的方式。在此提案中，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。我们将使用融合的突触囊泡的Styryl染料标记来量化由突触前G蛋白引起的突触前末端的不完全囊泡融合事件的持续时间？我们还希望通过测量和建模突触后受体激活的动力学来确定突触前受体激活对神经递质的时间和浓度的影响。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的特性的影响。