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

项目摘要 我们的最终目标是从机制上表征5-羟色胺5-HT2A(5HT2A)受体的基本作用和 代谢型谷氨酸2受体作为G蛋白偶联受体异构体的研究 在调节受体运输、信号传递和抗精神病药样行为方面。神经递质5-羟色胺 和谷氨酸都是精神病和抗精神病药物的相当关注的目标 发展。A家族5HT2A和C家族mGlu2是GPCR，它们与 精神分裂症和其他精神障碍的病理生理学和治疗。非典型的抗精神病药物， 如氯氮平、奥氮平和利培酮，都对5HT2a受体有很高的亲和力。 最近对啮齿动物进行的临床前试验表明，激活mGlu2受体的药物具有潜在的应用价值 新的抗精神病药物。我们以前的发现表明，5HT2A和mGlu2保持着密切的关系 异源系统和小鼠额叶皮质中的分子接近。使用以下组合 精神分裂症患者体外、动物模型和死后人脑的跨学科研究 我们提供的证据表明，5HT2A-mGlu2异构体受体复合体是肿瘤生长所必需的 非典型和谷氨酸类抗精神病药物引起的治疗反应，并可能参与 精神分裂症的皮质突起改变。为了更好地了解5HT2A-mGlu2 大脑功能的复杂性，以及开发更有效的抗精神病药物的基础，我们 建议描述其在细胞内运输和信号传递的基本分子机制， 以及研究需要5HT2a和5HT2a表达的抗精神病药样行为反应 MGlu2在小鼠体内作为GPCR异构体。我们的结果有望扩大我们对分子的理解。 精神病的基础，并可能提供一种途径，以确定新的和更有效的药物治疗 治疗精神分裂症和其他精神障碍。

Project Summary 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 psychotic disorders.