权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8618920
负责人：
QIANG WANG
金额：
$ 37.13万
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8618920
关键词：
Acute Address Affinity Amino Acids Amphetamines Antibodies Area Autoradiography Basal Ganglia Behavior Behavior Control Behavioral Binding Biochemical Brain C-terminal Cells Chronic Cognition Corpus striatum structure Development Disease model Drug Addiction Emotions Feedback Glutamate Receptor Glutamates Homer protein Immunoblotting In Vitro Injection of therapeutic agent Kinetics Life Link Liquid Chromatography Mediating Mental disorders Metabotropic Glutamate Receptors Modeling Molecular Motivation Motor Activity N-Methyl-D-Aspartate Receptors Neuraxis Neurons Peptides Pharmacotherapy Phosphorylation Phosphoserine Phosphothreonine Phosphotransferases Pilot Projects Plastics Post-Translational Regulation Property Protein Kinase Proteomics RNA Splicing Reaction Regulation Research Project Grants Rewards Role Series Serine Signal Transduction Site Small Interfering RNA Substance Addiction Synapses Tail Testing Variant addiction base behavioral sensitization calmodulin-dependent protein kinase II clinically relevant design drug of abuse in vivo innovation insight interdisciplinary approach mutant nano neurobehavioral novel protein protein interaction psychostimulant public health relevance receptor receptor function research study scaffold stem tandem mass spectrometry trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): Protein phosphorylation is an important mechanism for post-translational regulation of glutamate receptors. Through phosphorylating a specific amino acid in the intracellular domain, protein kinases regulate anchoring, trafficking, and signaling of a given glutamate receptor. Group I metabotropic glutamate receptors (mGluR1/5) are densely expressed in the striatum, a brain area involved in addictive properties of psychostimlants. The long-form mGluR1/5 splice variants (1a, 5a, and 5b) have a large intracellular C-terminal tail, which provides a basis for direct protein-protein interactions and phosphorylation. In our recent studies, we found that Ca2+/calmodulin-dependent protein kinase II (CaMKII) binds directly to the proximal region of mGluR5a C-terminus. This binding converts mGluR5a into a biochemical substrate for phosphorylation likely at a selective serine site. These findings raise innovative questions as to if CaMKII regulates mGluR1/5 via a direct protein-protein interaction and phosphorylation and if this regulation has a high clinical relevance in a disease model. In this continuation proposal, a series of coherent experiments from molecule to behavior was proposed to confirm the direct binding of CaMKII to mGluR1/5 in vitro and to establish that native CaMKII and mGluR1/5 interact with each other in striatal neurons in vivo. We will characterize if and how Ca2+ regulates the interaction between CaMKII and mGluR1/5 in vitro and in vivo. We will then investigate whether Ca2+-regulated CaMKII-mGluR1/5 interactions regulate 1) signaling efficacy of mGluR1/5, 2) trafficking of the receptors, and 3) interactions of mGluR1/5 with key scaffold Homer proteins, in striatal neurons or heterologous cells. Finally, we will carry out neurobehavioral experiments to define the role of CaMKII-mGluR1/5 interactions in the addictive action of the psychostimulant amphetamine. Our results will provide evidence and insights for a new synaptic model of kinase-regulated mGluRs and for its linkage to a mental illness (substance addiction). They will also ultimately contribute to the development of novel pharmacotherapies, by targeting mGluRs and CaMKII, for treating various mental illnesses, including addiction.

描述（由申请人提供）：蛋白质磷酸化是谷氨酸受体翻译后调节的重要机制。通过磷酸化细胞内结构域中的特定氨基酸，蛋白激酶调节给定谷氨酸受体的锚定、运输和信号传导。 I 类代谢型谷氨酸受体 (mGluR1/5) 在纹状体中密集表达，纹状体是与精神兴奋剂成瘾特性相关的大脑区域。长型 mGluR1/5 剪接变体（1a、5a 和 5b）具有较大的细胞内 C 末端尾部，为直接蛋白质-蛋白质相互作用和磷酸化提供了基础。在我们最近的研究中，我们发现 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 直接与 mGluR5a C 末端的近端区域结合。这种结合将 mGluR5a 转化为生化底物，可能在选择性丝氨酸位点进行磷酸化。这些发现提出了创新性问题：CaMKII 是否通过直接的蛋白质-蛋白质相互作用和磷酸化来调节 mGluR1/5，以及这种调节在疾病模型中是否具有高度的临床相关性。在这个延续提案中，提出了一系列从分子到行为的连贯实验，以在体外确认 CaMKII 与 mGluR1/5 的直接结合，并确定天然 CaMKII 和 mGluR1/5 在体内纹状体神经元中相互作用。我们将描述 Ca2+ 是否以及如何在体外和体内调节 CaMKII 和 mGluR1/5 之间的相互作用。然后，我们将研究纹状体神经元或异源细胞中 Ca2+ 调节的 CaMKII-mGluR1/5 相互作用是否调节 1) mGluR1/5 的信号传导功效，2) 受体的运输，以及 3) mGluR1/5 与关键支架 Homer 蛋白的相互作用。最后，我们将进行神经行为实验来确定 CaMKII-mGluR1/5 相互作用在精神兴奋剂安非他明成瘾作用中的作用。我们的结果将为激酶调节 mGluR 的新突触模型及其与精神疾病（物质成瘾）的联系提供证据和见解。他们还将最终通过针对 mGluR 和 CaMKII 来开发新型药物疗法，用于治疗各种精神疾病，包括成瘾。