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: 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
• 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

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定义特征。已知位于突触前末梢的受体深刻地抑制神经递质的释放。其中，G蛋白偶联受体普遍存在。我们已经证明，G蛋白偶联受体抑制突触传递的影响直接介导的核心复合物囊泡融合。Gbg直接结合到并入引发囊泡的SNARE复合物中的SNAP-25。我们现在假设，这种调制的机制是在融合孔动力学的突触囊泡释放到突触间隙的发射器的改变。这种传递方式的改变可能会对突触传递的实际工作方式以及我们对它的解释方式产生深远的影响。短暂融合，将在重复活动期间保存囊泡，它还可以通过支持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的模式。在这个提议中，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。我们将量化的持续时间不完整的囊泡融合事件从突触前G蛋白引起的突触前终端使用苯乙烯染料标记的融合突触囊泡？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中神经递质的时程和浓度的影响。我们还将确定改变这些参数将对不同突触后离子型受体的相对激活产生的影响。最后，我们将研究的影响，突触前G蛋白的个人突触接触的性能，使用高速成像技术。