Regulation of Vesicular Glutamate Transport

囊泡谷氨酸运输的调节

基本信息

批准号：
7278597
负责人：
Susan M. Voglmaier
金额：
$ 17.15万
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：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7278597
关键词：
Accounting Acidic Region Adult Affect Behavioral Brain C-terminal Carrier Proteins Cells Chimeric Proteins Chromosome Pairing Co-Immunoprecipitations Cytoplasm Data Drug Addiction Elements Endocytosis Epitopes Exhibits Exocytosis Family Functional disorder Glutamate Transporter Glutamates Glutathione S-Transferase Goals Hippocampus (Brain)Learning Length Lipids Long-Term Potentiation Maps Membrane Protein Traffic Memory Mental Depression Mentored Clinical Scientist Development Award (K08)Monitor Neurons Pattern Point Mutation Probability Process Property Protein Binding Domain Protein Isoforms Proteins Rate Recycling Regulation Research Personnel Role SH3 Domains Schizophrenia Signal Transduction Site-Directed Mutagenesis Speed Synapses Synaptic Vesicles Synaptic plasticity Testing Therapeutic Agents Ubiquitination Vesicle addiction excitatory neuron neurotransmission polyproline postsynaptic presynaptic programs protein protein interaction protein transport receptor receptor sensitivity research study size trafficking yeast two hybrid interaction screening

项目摘要

DESCRIPTION (provided by applicant): The changes in synaptic strength that underlie behavioral phenomena such as learning, memory and addiction, are usually attributed to postsynaptic changes in receptor sensitivity, but they may also reflect presynaptic regulation of the amount of transmitter released. The amount of glutamate per vesicle available for exocytotic release depends on its transport from the cytoplasm into vesicles by a family of vesicular glutamate transporter proteins, VGLUTs. VGLUT1 and 2, which account for the exocytotic release of glutamate by essentially all well-established excitatory neurons, exhibit a mutually exclusive pattern of expression in adult brain that correlates with the probability of transmitter release and the potential for plasticity. VGLUT1 also contains several protein-protein interaction domains not found in VGLUT2. The long-term goal of this K08 Mentored Clinical Scientist Development Award proposal is to understand how differences in the trafficking of VGLUT isoforms contribute to the differences in glutamate release observed at different synapses. The strategy is to study the role of C-terminal sequences in activity and trafficking of the different VGLUT isoforms. We have found that one of the polyproline motifs in the C-terminus of VGLUT1 interacts with proteins involved in synaptic vesicle recycling. We will characterize these interactions and determine whether they regulate glutamate transport by influencing vesicle filling, trafficking, or other aspects of the vesicle cycle. In addition, we will characterize and identify protein interactions with two other internalization motifs in VGLUT1. Together, these motifs may contribute to differences in the speed of vesicle filling, exocytosis and endocytosis in glutamate signaling. Increasing evidence implicates glutamate hypofunction in the pathophysiology of schizophrenia, which may involve changes in glutamate release. Thus, an understanding of the regulation of glutamate storage and release may be important in the targeting of therapeutic agents for schizophrenia

描述（由申请人提供）：学习、记忆和成瘾等行为现象背后的突触强度变化通常归因于受体敏感性的突触后变化，但它们也可能反映了突触前对递质释放量的调节。每个囊泡可用于胞吐释放的谷氨酸量取决于其通过囊泡谷氨酸转运蛋白家族 (VGLUT) 从细胞质转运到囊泡中的情况。 VGLUT1 和 2 负责几乎所有成熟的兴奋性神经元的谷氨酸胞吐释放，它们在成人大脑中表现出相互排斥的表达模式，与递质释放的概率和可塑性的潜力相关。 VGLUT1 还包含 VGLUT2 中未发现的几个蛋白质-蛋白质相互作用结构域。 K08 指导临床科学家发展奖提案的长期目标是了解 VGLUT 同工型运输的差异如何导致不同突触处观察到的谷氨酸释放差异。该策略是研究 C 端序列在不同 VGLUT 同工型的活性和运输中的作用。我们发现 VGLUT1 C 末端的聚脯氨酸基序之一与参与突触小泡回收的蛋白质相互作用。我们将描述这些相互作用的特征，并确定它们是否通过影响囊泡填充、运输或囊泡周期的其他方面来调节谷氨酸转运。此外，我们将表征并鉴定与 VGLUT1 中其他两个内化基序的蛋白质相互作用。总之，这些基序可能导致谷氨酸信号传导中囊泡填充、胞吐作用和内吞作用的速度差异。越来越多的证据表明谷氨酸功能减退与精神分裂症的病理生理学有关，这可能涉及谷氨酸释放的变化。因此，了解谷氨酸储存和释放的调节对于精神分裂症治疗药物的靶向治疗可能很重要