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

描述(由申请人提供)：我们的最终目标是从机械上表征5-羟色胺5-羟色胺(5-HT2A)受体和代谢性谷氨酸2(MGlu2)受体作为G蛋白偶联受体(GPCR)异构体复合体在调节受体运输、信号传递和抗精神病药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的重要靶点。A家族5HT2A和C家族mGlu2是与精神分裂症和其他精神障碍的病理生理学和治疗有关的GPCRs。非典型抗精神病药物，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受体的药物代表着潜在的抗精神病药物。我们以前的发现表明，5HT2A和mGlu2在异源系统和小鼠额叶皮质中保持着密切的分子亲和力。采用多学科方法相结合的方法，在体外、动物模型和精神分裂症患者的死后人脑中，我们提供了证据表明，5HT2A-mGlu2异构体受体复合体是非典型抗精神病药物和谷氨酸抗精神病药物诱导的治疗反应所必需的，并可能参与精神分裂症皮质过程的改变。为了提供 为了更好地了解5HT2A-mGlu2复合体在脑功能中的作用，以及开发更有效的抗精神病药物的基础，我们建议表征其在细胞内转运和信号传递的基本分子机制，并研究在小鼠中需要表达5HT2A和mGlu2作为GPCR异构体的抗精神病药样行为反应。我们的结果有望扩大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障碍的新的、更有效的药物提供一条途径。

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.