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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：
8630649
负责人：
Javier González-Maeso
金额：
$ 42.25万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2009-01-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630649
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 GTP-Binding Proteins Geographic Locations Glutamates Goals HTR2A gene Histone Acetylation Histone Deacetylase Inhibitor Human Image 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 Population Prevalence Prevention Process Psychotic Disorders Receptor Signaling Risperidone Rodent Role Route Schizophrenia Sensory Receptors Serotonin Signal Transduction Simplexvirus Structure System Therapeutic Up-Regulation Virus Vorinostat Work atypical antipsychotic base chromatin immunoprecipitation drug development frontal lobe hippocampal pyramidal neuron histone deacetylase 2 histone modification human CCR10 protein improved interdisciplinary approach metabotropic glutamate receptor 2 olanzapine pre-clinical prevent promoter protein activation public health relevance receptor response trafficking

项目摘要

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.

项目总结