Membrane Trafficking of Vesicular Neurotransmitter Transporters

囊泡神经递质转运蛋白的膜运输

• 批准号: 8448313
• 负责人: Susan M. Voglmaier
• 金额: $ 37.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448313
• 关键词: Accounting; Adaptor Signaling Protein; Affect; Amino Acid Sequence; Anxiety Disorders; Back; Behavior; Biochemical; Biochemistry; Biogenesis; Brain; C-terminal; Carrier Proteins; Cells; Cellular Membrane; Characteristics; Chemicals; Cognition; Color; Communication; Competence; Consensus Sequence; Data; Depressed mood; Development; Disease; Electron Microscopy; Electrophysiology (science); Emotions; Environment; Epilepsy; Exocytosis; Fluorescence; Frequencies; Generations; Glutamate Transporter; Glutamates; Goals; Image; Individual; Kinetics; Life; Location; Maintenance; Mediating; Membrane; Membrane Protein Traffic; Membrane Proteins; Modeling; Modification; Molecular; Mus; Nerve; Neurons; Neurotransmitters; Optical reporter; Optics; Output; PHluorin; Pathway interactions; Pattern; Peptide Sequence Determination; Physiological; Play; Probability; Process; Property; Protein Isoforms; Proteins; Recycling; Regulation; Research; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Site; Sorting - Cell Movement; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Testing; Therapeutic Intervention; Transgenes; Variant; Vesicle; cellular imaging; chemical release; design; improved; information processing; insight; neuropsychiatry; neurotransmitter release; novel therapeutics; research study; response; therapy development; trafficking

DESCRIPTION (provided by applicant): Synaptic transmission involves the transformation of electrical into chemical signals by the regulated release of neurotransmitter from synaptic vesicles. High frequency synaptic transmission depends on the recycling of neurotransmitter back into the nerve terminal after release, where it is re-packaged into synaptic vesicles by vesicular neurotransmitter transporter proteins located in the vesicle membrane. Repetitive neurotransmitter release also requires mechanisms to recycle synaptic vesicle membrane and proteins locally at the nerve terminal. Variation in the kinetics of synaptic vesicle recycling may shape the amount and pattern of neurotransmitter output, and hence contribute to information processing and synaptic plasticity. The distribution of vesicles in functional pools, defined by their location and fusion probability, can also influence neurotransmitter release in response to repetitive firing. Multiple pathways have been proposed for the recycling of synaptic vesicle components after exocytosis, but the relationship of these pathways to the different synaptic vesicle pools has remained unclear. Synaptic vesicle proteins have been assumed to undergo recycling as a unit. However, emerging data indicates that differences in the association with distinct endocytic adaptor proteins may influence the trafficking of individual synaptic vesicle proteins, affecting the composition of synaptic vesicles and hence their functional characteristics. The long-term goal of the proposed research is to understand how membrane trafficking of individual vesicular proteins influences the protein composition of synaptic vesicles, the maintenance of synaptic vesicle pools, and the release of transmitter by specific circuits. The strategy of this proposal is to study the trafficking of synaptic vesicle proteins by a combination of biochemistry, live cell imaging, electrophysiology, and electron microscopy. Fusions of vesicular neurotransmitter transporters with pH-sensitive fluorescent proteins provide optical probes to study the effect of protein interactions and regulatory mechanisms on the recycling pathways of vesicular transporter proteins. The specific aims of this proposal are designed to study the regulation of trafficking of vesicular glutamate transporters VGLUT1 and 2 by 1) characterizing differences in the trafficking of two closely related isoforms, 2) identifying the protein determinants and 3) biochemical and cellular mechanisms underlying VGLUT recycling. Regulation of neurotransmitter release may be an important approach to therapeutic intervention and the molecular machinery new targets for the development of better treatments for neuropsychiatric disorders such as epilepsy, schizophrenia, and anxiety disorders.

描述（由申请人提供）：突触传播涉及通过从突触囊泡中释放神经递质的调节神经递质向化学信号转化。高频突触传播取决于神经递质在释放后将神经递质的回收回到神经末端，在该囊泡膜中，它通过囊泡神经递质转运蛋白将其重新包装成突触囊泡中。重复的神经递质释放还需要机制，以在神经末端回收突触囊泡膜和蛋白质。突触囊泡回收动力学的变化可能会影响神经递质输出的数量和模式，因此有助于信息处理和突触可塑性。囊泡在功能池中的分布（由其位置和融合概率定义）也会影响神经递质的释放，以响应重复性射击。已经提出了多种途径，用于在胞吞后的突触囊泡成分回收，但是这些途径与不同突触囊泡池的关系尚不清楚。已经假定突触囊泡蛋白作为一个单位进行回收。但是，新兴数据表明，与独特的内吞衔接蛋白关联的差异可能会影响单个突触囊泡蛋白的运输，从而影响突触囊泡的组成，从而影响其功能特征。拟议研究的长期目标是了解单个囊泡蛋白的膜运输如何影响突触囊泡的蛋白质组成，维持突触囊泡池以及通过特定电路释放发射机。该建议的策略是通过生物化学，活细胞成像，电生理学和电子显微镜的结合研究突触囊泡蛋白的运输。囊泡神经递质转运蛋白与pH敏感荧光蛋白的融合提供了光学探针，以研究蛋白质相互作用和调节机制对囊泡转运蛋白的回收途径的影响。该提案的具体目的旨在研究调节囊泡谷氨酸转运蛋白vglut1和2 x 1）的调节。神经递质释放的调节可能是治疗干预的重要方法，以及分子机械的新靶标，用于开发更好的神经精神疾病治疗，例如癫痫，精神分裂症和焦虑症。