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制上表征5-羟色胺5-HT2A （5HT2A）受体和代谢性谷氨酸2 （mGlu2）受体作为G蛋白偶联受体（GPCR）异聚体复合物在调节受体运输、信号传导和抗精神病样行为中的重要作用。神经递质血清素和谷氨酸都是精神病和抗精神病药物开发中相当关注的目标。家族A 5HT2A和家族C mGlu2是与精神分裂症和其他精神障碍的病理生理和治疗有关的gpcr。非典型抗精神病药物，如氯氮平、奥氮平和利培酮，都具有对5HT2A受体的高亲和力。最近在啮齿动物中的临床前试验表明，激活mGlu2受体的药物代表了潜在的新型抗精神病药物。我们之前的研究结果表明，5HT2A和mGlu2在异源系统和小鼠额叶皮层中保持密切的分子接近性。结合跨学科的方法，在体外、动物模型和死后的精神分裂症受试者的大脑中，我们提供了证据，证明5HT2A-mGlu2异源受体复合物是非典型和谷氨酸类抗精神病药物诱导的治疗反应所必需的，并且可能参与精神分裂症皮质过程的改变。为了提供

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.