Membrane Trafficking of Vesicular Neurotransmitter Transporters

囊泡神经递质转运蛋白的膜运输

• 批准号: 10053339
• 负责人: Susan M. Voglmaier
• 金额: $ 37.74万
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053339
• 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

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.

谷氨酸能神经传递的功能障碍与许多神经精神疾病有关，包括 精神分裂症，癫痫和自闭症。尽管突触后受体受到了最大的关注，但 控制谷氨酸释放的突触前机制也是有前途的治疗靶标，但已经是 不太适合学习。突触囊泡胞吐释放谷氨酸释放取决于谷氨酸包装 并通过囊泡谷氨酸转运蛋白（VGLUTS）介导的回收利用。 VGLUT1和2同工型展示 区分皮质（VGLUT1）和皮层下（VGLUT2）的成人大脑中的互补表达 连接。使用谷氨酸传播，VGLUT1和2-荧光素的遗传编码的光学报道， 我们已经表征了同工型特异性排序信号和蛋白质相互作用，这些相互作用介导了差异 VGLUT1和2贩运。以前与突触囊泡蛋白无关的蛋白质的参与 可能暗示了囊泡回收的新型机制。同工型上游的突触前信号网络 - 特定的vglut贩运为在离散大脑中差异调节谷氨酸释放提供了机会 途径，并确定新型的治疗靶标，以使神经精神疾病中的脑回路正常化。这些 机制也可能差异地取决于神经元的发射率，从而使多余 活动同时可以进行正常的生理传播。拟议的长期目标 研究是要了解膜流囊蛋白的膜运输如何影响蛋白质 突触囊泡的组成，突触囊泡的维护以及通过 特定电路。该建议的策略是研究同工型特异性上游的信号通路 VGLUT突触囊泡回收。该提案的具体目的旨在研究 通过1）表征VGLUT1回收的调节，对囊泡谷氨酸转运蛋白进行贩运 泛素连接酶相互作用，2）表征肌醇六磷酸对VGLUT2回收的调节 激酶和3）表征同工型特异性运输如何改变突触发展。作为关键 突触传播的介体，这些囊泡蛋白以及调节其表达的因素， 本地化和活动会极大地影响神经递质的释放，使它们有前途 治疗靶标。神经递质释放的调节可能是治疗的重要方法 干涉。分子机械为开发更好的治疗方法提供了新的目标 神经精神疾病。