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：
10291414
负责人：
Susan M. Voglmaier
金额：
$ 37.06万
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 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291414
关键词：
Adaptor Signaling Protein Adult Affect Antipsychotic Agents Anxiety Disorders Attention Behavior Binding Biochemical Brain Brain region Cells Clathrin Adaptors Cognition Communication Cytoplasm Development Diphosphates Dominant-Negative Mutation Emotions Endocytosis Epilepsy Equilibrium Event Exhibits Exocytosis Functional disorder Genetic Glutamate Transporter Glutamates Goals Hippocampus (Brain)In Vitro Individual Inositol Kinetics Knock-out Ligase Maintenance Mediating Mediator of activation protein Membrane Modeling Molecular Neurons Neurotransmitters Optical reporter PHluorin Pathway interactions Pattern Pharmacology Physiological Physiology Population Presynaptic Terminals Probability Process Progress Reports Property Protein Isoforms Proteins Recycling Regulation Research Role Schizophrenia Signal Pathway Signal Transduction Signaling Protein Sorting - Cell Movement Synapses Synaptic Transmission Synaptic Vesicles Testing Thalamic structure Therapeutic Intervention Ubiquitination Vesicle Work autism spectrum disorder brain pathway chemical release course development design excitatory neuron inositol hexakisphosphate kinase knock-down neuropsychiatric disorder neurotransmission neurotransmitter release new therapeutic target novel polyproline postsynaptic presynaptic receptor synaptogenesis therapeutic target therapy development trafficking transmission process ubiquitin ligase ubiquitin-protein ligase vesicular glutamate transporter 1

项目摘要

Dysfunction of glutamatergic neurotransmission is implicated in many neuropsychiatric disorders, including schizophrenia, epilepsy and autism. Although postsynaptic receptors have received the most attention, presynaptic mechanisms controlling glutamate release are also promising therapeutic targets, but have been less amenable to study. Glutamate release by synaptic vesicle exocytosis depends on glutamate packaging and recycling mediated by vesicular glutamate transporters (VGLUTs). VGLUT1 and 2 isoforms exhibit complementary expression in adult brain that distinguishes cortical (VGLUT1) and subcortical (VGLUT2) connections. Using genetically encoded optical reporters of glutamate transmission, VGLUT1 and 2-pHluorins, we have characterized the isoform-specific sorting signals and protein interactions that mediate differences in VGLUT1 and 2 trafficking. The involvement of proteins previously not associated with synaptic vesicle proteins may suggest novel mechanisms for vesicle recycling. Presynaptic signaling networks upstream of isoform- specific VGLUT trafficking present an opportunity to differentially modulate glutamate release in discrete brain pathways, and identify novel therapeutic targets to normalize brain circuits in neuropsychiatric disease. These mechanisms may also differentially depend on neuronal firing rate, offering the possibility of dampening excess activity while allowing normal physiological transmission to proceed. 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 signaling pathways upstream from isoform-specific VGLUT synaptic vesicle recycling. The specific aims of this proposal are designed to study the regulation of trafficking of vesicular glutamate transporters by 1) characterizing the modulation of VGLUT1 recycling by ubiquitin ligase interactions, 2) characterizing modulation of VGLUT2 recycling by inositol hexakisphosphate kinases, and 3) characterizing how isoform-specific trafficking changes over synapse development. As key mediators of synaptic transmission, these vesicular proteins and the factors that modulate their expression, localization and activity can dramatically influence neurotransmitter release, making them promising therapeutic targets. Regulation of neurotransmitter release may be an important approach to therapeutic intervention. The molecular machinery offers new targets for the development of better treatments for neuropsychiatric disorders.

谷氨酸能神经传递功能障碍与许多神经精神疾病有关，包括精神分裂症、癫痫症和自闭症。尽管突触后受体受到了最多的关注，控制谷氨酸释放的突触前机制也是有希望的治疗靶点，但已被不太适合学习。突触小泡胞吐作用释放的谷氨酸取决于谷氨酸包装以及由囊泡谷氨酸转运蛋白（VGLUT）介导的回收。 VGLUT1 和 2 亚型表现出成人大脑中区分皮质 (VGLUT1) 和皮质下 (VGLUT2) 的互补表达连接。使用谷氨酸传输的基因编码光学报告基因、VGLUT1 和 2-pHluorins，我们已经表征了介导亚型差异的亚型特异性分选信号和蛋白质相互作用 VGLUT1 和 2 贩运。以前与突触小泡蛋白无关的蛋白质的参与可能提出了囊泡回收的新机制。异构体上游的突触前信号网络特定的 VGLUT 运输提供了差异调节离散大脑中谷氨酸释放的机会途径，并确定新的治疗靶点以使神经精神疾病的脑回路正常化。这些机制也可能不同地依赖于神经元放电率，从而提供抑制过度放电的可能性活动，同时允许正常的生理传输进行。拟议的长期目标研究的目的是了解单个囊泡蛋白的膜运输如何影响蛋白质突触小泡的组成、突触小泡池的维持以及递质的释放具体电路。该提案的策略是研究异构体特异性上游的信号通路 VGLUT 突触小泡回收。该提案的具体目的是研究监管囊泡谷氨酸转运蛋白的运输通过 1) 表征 VGLUT1 回收的调节泛素连接酶相互作用，2) 表征肌醇六磷酸对 VGLUT2 回收的调节激酶，3) 描述异构体特异性运输在突触发育过程中如何变化。作为关键突触传递的介质，这些囊泡蛋白以及调节其表达的因素，定位和活动可以极大地影响神经递质的释放，使其具有广阔的前景治疗目标。调节神经递质释放可能是治疗的重要方法干涉。分子机器为开发更好的治疗方法提供了新的目标神经精神疾病。