Molecular Regulation of Metabotropic Glutamate Receptors in Striatal Neurons

纹状体神经元代谢型谷氨酸受体的分子调控

基本信息

批准号：
9027878
负责人：
QIANG WANG
金额：
$ 37.75万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-12-01 至 2020-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9027878
关键词：
Adult Affinity Agonist Animals Attention Behavior Binding Biochemical Reaction Biochemistry Biology Brain C-terminal Cells Chronic stress Corpus striatum structure Coupling Depressive disorder Development Disease Distal Dopamine Dopamine D1 Receptor Electrophysiology (science)Event Excitatory Synapse Functional disorder Glutamate Receptor Health In Vitro Knowledge Major Depressive Disorder Maps Mediating Mental Depression Mental disorders Metabotropic Glutamate Receptors Modeling Molecular Monitor Moods N-Methyl-D-Aspartate Receptors Neurons Nucleus Accumbens Pathogenesis Peptides Pharmacotherapy Phosphorylation Phosphorylation Site Phosphotransferases Physiology Pilot Projects Property Protein Chemistry Protein Tyrosine Kinase Proteins Proto-Oncogene Proteins c-fyn Psyche structure Rattus Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Research Research Project Grants Rewards Role Scaffolding Protein Series Signal Transduction Site Small Interfering RNA Social isolation Specificity Subgroup Substrate Specificity Surface System Tail Testing Time Tyrosine Tyrosine Kinase Inhibitor Tyrosine Phosphorylation behavioral plasticity behavioral response depressive symptoms in vivo interdisciplinary approach metabotropic glutamate receptor 5 mutant neuroadaptation neurochemistry new therapeutic target novel prevent receptor receptor function research study response trafficking

项目摘要

DESCRIPTION (provided by applicant): Several non-receptor tyrosine kinases (nRTK) are highly expressed in the brain and are pivotal for brain functions and some mental diseases. Among brain-enriched nRTKs, Fyn draws the most attention. Recently, we found that Fyn directly binds to metabotropic glutamate receptor 5 (mGluR5), which enables Fyn to phosphorylate mGluR5 at a tyrosine site in the intracellular C-terminus (CT). These findings for the first time reveal mGluR5 as a direct substrate of Fyn. Encouraged by this new discovery, we propose this renewal application to further study the Fyn regulation of mGluR5 and to define roles of Fyn and mGluR1/5 in the pathogenesis and symptomology of a common mental illness. Our hypothesis is that Fyn binds and phosphorylates mGluR1/5 to control receptor function and promote depression-like behaviors. Using multidisciplinary approaches, this hypothesis will be tested both in vitro and in vivo, as appropriate, in the following four inter-supportive Aims. Aim will characterize fundamental kinase-substrate biochemistry between Fyn and mGluR1/5 in vitro. Aim II will define the regulation of Fyn-mGluR1/5 interactions and tyrosine phosphorylation of mGluR1/5 by changing dopamine inputs in striatal neurons in vivo. Aim III will explore functional roles of Fyn-mediated phosphorylation in the modulation of trafficking and subcellular expression of mGluR1/5 and the efficacy of receptor signaling in striatal neurons. Aim IV will firs monitor neuroadaptations of striatal Fyn-mGluR1/5 interactions and mGluR1/5 phosphorylation in response to prolonged social isolation in adult rats, a chronic stress paradigm modeling anhedonic depression in adulthood animals. Aim IV will then clarify the functional role of Fyn-mGluR1/5 interactions in isolation-induced depression-like behaviors. Results achieved here will conceptually advance our current understanding of the phosphorylation-dependent regulation of glutamate receptor signaling. They will also ultimately contribute to the development of novel pharmacotherapies, by targeting an nRTK (Fyn) and mGluR1/5, for the treatment of some core symptoms of depression.

描述（由适用提供）：几种非受体酪氨酸激酶（NRTK）在大脑中高度表达，对于大脑功能和某些精神疾病是关键的。在富含脑部的NRTK中，Fyn引起了最大的关注。最近，我们发现FYN直接与代谢型谷氨酸受体5（MGLUR5）结合，该Fyn能够在细胞内C-末端（CT）中的酪氨酸位点磷酸化MGLUR5。这些发现首次揭示了MGLUR5作为FYN的直接底物。在这一新发现的鼓励下，我们提出了这种更新应用，以进一步研究MGLUR5的FYN调节，并确定FYN和MGLUR1/5在常见精神疾病的发病机理和症状中的作用。我们的假设是FYN结合并磷酸化MGLUR1/5以控制受体功能并促进抑郁样行为。使用多学科的方法，在以下四个支持性的目标中，该假设将在体外和体内进行测试。 AIM将在体外表征Fyn和Mglur1/5之间的基本激酶 - 基底生物化学。 AIM II将通过改变体内纹状体神经元的多巴胺输入来定义FYN-MGLUR1/5相互作用和MGLUR1/5的酪氨酸磷酸化的调节。 AIM III将探索FYN介导的磷酸化在AIM IV调节中的功能作用，然后阐明Fyn-MGlUR1/5相互作用和MGLUR1/5磷酸化的功能作用，响应于成年大鼠的长期社会隔离，而成年大鼠的长期社会隔离，成年动物中的慢性压力态度范围内的成年动物抑制作用。 AIM IV然后将阐明FYN-MGLUR1/5相互作用在孤立诱导的抑郁样行为中的功能作用。在这里取得的结果将在概念上提高我们对谷氨酸受体信号磷酸化依赖性调节的当前理解。他们还将通过靶向NRTK（FYN）和MGLUR1/5来治疗某些抑郁症的核心症状，最终将通过靶向NRTK（FYN）和MGLUR1/5来为新型药物疗法的发展做出贡献。