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

• 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
• 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

 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（由申请人提供）：几种非受体酪氨酸激酶（nRTK）在脑中高度表达，对脑功能和某些精神疾病至关重要。在大脑丰富的nRTK中，Fyn引起了最多的关注。最近，我们发现Fyn直接与代谢型谷氨酸受体5（mGluR 5）结合，这使得Fyn能够在细胞内C末端（CT）的酪氨酸位点磷酸化mGluR 5。这些发现首次揭示了mGluR 5作为Fyn的直接底物。受这一新发现的鼓舞，我们提出了这一更新申请，以进一步研究Fyn对mGluR 5的调节，并确定Fyn和mGluR 1/5在常见精神疾病的发病机制和病理学中的作用。我们的假设是Fyn结合并磷酸化mGluR 1/5以控制受体功能并促进抑郁样行为。使用多学科方法，将在体外和体内（如适用）对该假设进行检验，以实现以下四个相互支持的目标。目的将在体外表征Fyn和mGluR 1/5之间的基本激酶底物生物化学。目的二：研究纹状体多巴胺对Fyn-mGluR 1/5相互作用及mGluR 1/5酪氨酸磷酸化的影响。目的探讨Fyn介导的磷酸化在纹状体神经元mGluR 1/5转运和亚细胞表达调节中的功能作用以及受体信号传导的功效。目的IV将首先监测纹状体Fyn-mGluR 1/5相互作用和mGluR 1/5磷酸化对成年大鼠长期社会隔离的神经适应，这是一种模拟成年动物快感缺失抑郁的慢性应激范式。目的IV将阐明Fyn-mGluR 1/5相互作用在隔离诱导的抑郁样行为中的功能作用。这里取得的结果将在概念上推进我们目前的理解磷酸化依赖的调节谷氨酸受体信号。他们还将最终通过靶向nRTK（Fyn）和mGluR 1/5来促进新型药物疗法的开发，用于治疗抑郁症的一些核心症状。