Membrane Trafficking of Vesicular Neurotransmitter Transporters

囊泡神经递质转运蛋白的膜运输

基本信息

批准号：
8644895
负责人：
Susan M. Voglmaier
金额：
$ 38.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8644895
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

项目摘要

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）：突触传递涉及通过突触小泡调节神经递质的释放将电信号转化为化学信号。高频突触传递依赖于神经递质释放后循环回到神经末梢，并通过位于囊泡膜上的囊泡神经递质转运蛋白重新包装到突触囊泡中。重复的神经递质释放还需要在神经末梢局部回收突触小泡膜和蛋白质的机制。突触小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，从而有助于信息处理和突触可塑性。功能池中囊泡的分布（由其位置和融合概率定义）也可以影响响应重复放电的神经递质释放。已经提出了胞吐作用后突触小泡成分回收的多种途径，但这些途径与不同突触小泡池的关系仍不清楚。突触小泡蛋白被认为作为一个单元进行回收。然而，新出现的数据表明，与不同内吞接头蛋白关联的差异可能会影响单个突触小泡蛋白的运输，从而影响突触小泡的组成，从而影响其功能特征。该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、突触囊泡池的维持以及特定电路释放递质。该提案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来研究突触小泡蛋白的运输。囊泡神经递质转运蛋白与 pH 敏感荧光蛋白的融合为研究蛋白质相互作用和调节机制对囊泡转运蛋白回收途径的影响提供了光学探针。该提案的具体目标是研究囊泡谷氨酸转运蛋白 VGLUT1 和 2 的运输调节，1) 表征两种密切相关的亚型运输的差异，2) 识别蛋白质决定因素，3) VGLUT 背后的生化和细胞机制回收。神经递质释放的调节可能是治疗干预的重要方法，也是开发更好的神经精神疾病（如癫痫、精神分裂症和焦虑症）治疗方法的分子机制新目标。