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Structure and function of the 5HT2A-mGlu2 heteromer in schizophrenia

5HT2A-mGlu2 异聚体在精神分裂症中的结构和功能

基本信息

批准号：
9293907
负责人：
Javier González-Maeso
金额：
$ 36.2万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293907
关键词：
Affect Affinity Agonist Animal Model Antipsychotic Agents Attention Attenuated Autopsy Behavior Behavioral Binding Biological Assay Brain Cells Chronic Clozapine Complex Confocal Microscopy Coupled Coupling Data Development Electron Microscopy Epigenetic Process Family Flow Cytometry Foundations Functional disorder G-Protein-Coupled Receptors G-substrate GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Geographic Locations Glutamates Goals HDAC2 gene HTR2A gene Histone Acetylation Histone Deacetylase Inhibitor Human In Vitro Knock-out Lead Ligand Binding Ligands Link Mediating Mental disorders Molecular Molecular Mechanisms of Action Mus Mutation Neurotransmitter Receptor Neurotransmitters Pathway interactions Pattern Pharmaceutical Preparations Pharmacotherapy Population Prevalence Prevention Process Psychotic Disorders Receptor Signaling Risperidone Rodent Role Route Schizophrenia Sensory Receptors Serotonin Serotonin Receptor 5-HT2A Signal Transduction Structure System Therapeutic Treatment Efficacy Up-Regulation Virus Vorinostat atypical antipsychotic behavioral response chromatin immunoprecipitation drug development frontal lobe hippocampal pyramidal neuron histone deacetylase 2 histone modification improved interdisciplinary approach microscopic imaging olanzapine overexpression pre-clinical prevent promoter protein activation public health relevance receptor response trafficking treatment response

项目摘要

DESCRIPTION (provided by applicant): Our final goal is to mechanistically characterize the essential role of the serotonin 5-HT2A (5HT2A) receptor and the metabotropic glutamate 2 (mGlu2) receptor as a G protein-coupled receptor (GPCR) heteromeric complex in regulating receptor trafficking, signaling, and antipsychotic-like behavior. The neurotransmitters serotonin and glutamate both have been the target of considerable attention regarding psychosis and antipsychotic drug development. Family A 5HT2A and family C mGlu2 are GPCRs that have been implicated in the pathophysiology and treatment of schizophrenia and other psychotic disorders. Atypical antipsychotic drugs, such as clozapine, olanzapine and risperidone, all have in common a high affinity for the 5HT2A receptor. Recent preclinical assays in rodents suggest that drugs that activate the mGlu2 receptor represent potential new antipsychotic medications. Our previous findings demonstrate that 5HT2A and mGlu2 maintain close molecular proximity in heterologous systems and in mouse frontal cortex. Using the combination of interdisciplinary approaches in vitro, in animal models and in postmortem human brain of schizophrenic subjects, we provide evidence that the 5HT2A-mGlu2 heteromeric receptor complex is necessary for the therapeutic responses induced by atypical and glutamate antipsychotic drugs, and is potentially involved in the altered cortical processes of schizophrenia. In order to provide a better understanding of the 5HT2A-mGlu2 complex in brain function, and the foundation for the development of more effective antipsychotic drugs, we propose to characterize the basic molecular mechanisms involved in its intracellular trafficking and signaling, as well as to investigate the antipsychotic-like behavioral responses that require expression of 5HT2A and mGlu2 as a GPCR heteromer in mouse. Our results are expected to extend our understanding of the molecular basis of psychosis, and may provide a route to the identification of new and more effective drugs for the treatment of schizophrenia and other psychiatric disorders.

描述（由申请人提供）：我们的最终目标是从机制上表征5-羟色胺5-HT 2A（5 HT 2A）受体和代谢型谷氨酸2（mGlu 2）受体作为G蛋白偶联受体（GPCR）异聚体复合物在调节受体转运、信号传导和抗精神病样行为中的重要作用。神经递质5-羟色胺和谷氨酸都是精神病和抗精神病药物开发方面相当关注的目标。家族A 5 HT 2A和家族C mGlu 2是涉及精神分裂症和其他精神障碍的病理生理学和治疗的GPCR。非典型的抗精神病药物，如氯氮平、奥氮平和利培酮，都对5 HT 2A受体具有高亲和力。最近在啮齿动物中的临床前试验表明，激活mGlu 2受体的药物代表了潜在的新的抗精神病药物。我们以前的研究结果表明，5 HT 2A和mGlu 2保持密切的分子接近在异源系统和小鼠额叶皮层。使用跨学科的方法相结合，在体外，在动物模型和精神分裂症患者的死后人脑，我们提供的证据表明，5 HT 2A-mGlu 2异聚体受体复合物是必要的非典型和谷氨酸类抗精神病药物诱导的治疗反应，并可能参与精神分裂症的皮质过程的改变。以此为您提供为了更好地了解5 HT 2A-mGlu 2复合物在脑功能中的作用，并为开发更有效的抗精神病药物奠定基础，我们拟表征其细胞内运输和信号传导的基本分子机制，并研究小鼠中需要表达5 HT 2A和mGlu 2作为GPCR异聚体的抗精神病样行为反应。我们的研究结果有望扩展我们对精神病分子基础的理解，并可能为识别治疗精神分裂症和其他精神疾病的新的和更有效的药物提供途径。