Structure and function of the 5HT2A/mGluR2 complex in schizophrenia

精神分裂症中 5HT2A/mGluR2 复合物的结构和功能

• 批准号: 8063085
• 负责人: Javier González-Maeso
• 金额: $ 41.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063085
• 关键词: Affect; Affinity; Agonist; Animal Model; Antipsychotic Agents; Autopsy; Behavior; Behavioral; Binding; Bioluminescence; Brain; Brain Diseases; Cells; Chronic; Clinical; Clozapine; Co-Immunoprecipitations; Cognition; Complex; Development; Emotions; Energy Transfer; Fluorescence; Fluorescence Resonance Energy Transfer; Future; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; Glutamates; HTR2A gene; Hallucinations; Hallucinogens; Health; Heterotrimeric GTP-Binding Proteins; Human; In Vitro; Link; Lysergic Acid Diethylamide; Mediating; Medical; Mental disorders; Mescaline; Molecular; Molecular and Cellular Biology; Mus; Neurons; Neurotransmitters; Patients; Pattern; Perception; Pharmaceutical Preparations; Population; Process; Psychotic Disorders; Research; Role; Route; Schizophrenia; Sensory Receptors; Serotonin; Serotonin Receptor 5-HT2C; Signal Pathway; Signal Transduction; Societies; Specificity; Staging; Structure; Symptoms; System; Validation; atypical antipsychotic; base; drug development; hippocampal pyramidal neuron; in vivo; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3; mouse model; neurochemistry; novel; receptor; research study; response

DESCRIPTION (provided by applicant): One of the guiding objectives of modern schizophrenia research is to build a bridge from molecular and cellular biology to the clinical symptoms of this psychotic mental disorder. Monoaminergic neurotransmitters have been the principal focus of schizophrenia research for many decades. Several approaches have also linked the neurotransmitter glutamate to the neurochemical alterations in patients with schizophrenia. Notably, clozapine and other atypical antipsychotics have high affinity for serotonin 5-HT2A receptors (2AR), and metabotropic glutamate receptors 2/3 (mGluR2/3) agonists have recently shown efficacy in treating schizophrenia. We identify a novel and unexpected functional brain 2AR/mGluR2 receptor complex that may unify the anti- serotonin and glutamatergic therapies of schizophrenia. Our results based on in vitro, animal models and postmortem human brain of schizophrenic subjects suggest that this 2AR/mGluR2 complex may be responsible for some psychotic symptoms in schizophrenia, and that it is the direct target of these two different classes of antipsychotic drugs. In order to understand the role of the 2AR/mGluR2 complex in brain function and to set the stage for future drug development we will pursue two aims. We will use in vitro studies in conjunction with cutting-edge computational approaches to investigate the molecular determinants at the interaction interface responsible for 2AR/mGluR2 complex stabilization and functional crosstalk. In cortical primary cultures and in vivo in mouse models we will study the neuronal signaling and behavior dependent on 2AR/mGluR2 complex function. Results of the proposed studies have the potential to provide a greater understanding of the structure and function of the 2AR/mGluR2 complex than is currently available for any G protein-coupled receptor heterocomplex, and may provide the basis for new pharmacological approaches to the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic, debilitating psychotic mental disorder that affects about one percent of the population in the U.S.A., and the seventh most costly medical illness to our society. We have discovered a new neuroreceptor complex that induces hallucinations in mouse, and is affected in schizophrenia brain. The characterization of the structure of the neuroreceptor will extend our understanding of the molecular basis of psychosis, and may provide a route to the development of new, more effective drugs for the treatment of schizophrenia.

描述(申请人提供)：现代精神分裂症研究的指导目标之一是建立一座从分子和细胞生物学到这种精神病精神障碍的临床症状的桥梁。单胺类神经递质几十年来一直是精神分裂症研究的主要焦点。几种方法也将神经递质谷氨酸与精神分裂症患者的神经化学变化联系起来。值得注意的是，氯氮平和其他非典型抗精神病药物对5-HT2A受体(2AR)有很高的亲和力，代谢性谷氨酸受体2/3(mGluR2/3)激动剂最近显示出治疗精神分裂症的效果。我们发现了一种新的和意想不到的脑2AR/mGluR2受体复合体，它可能统一了精神分裂症的抗5-羟色胺和谷氨酸能治疗。我们基于精神分裂症患者的体外、动物模型和死后人脑的研究结果表明，这种2AR/mGluR2复合体可能与精神分裂症的某些精神症状有关，是这两类不同类型抗精神病药物的直接靶点。为了了解2AR/mGluR2复合体在脑功能中的作用，并为未来的药物开发奠定基础，我们将追求两个目标。我们将使用体外研究结合前沿的计算方法来研究在相互作用界面上负责2AR/mGluR2复合体稳定和功能串扰的分子决定因素。在皮质原代培养和活体小鼠模型中，我们将研究依赖2AR/mGluR2复合体功能的神经元信号和行为。拟议的研究结果有可能比目前任何G蛋白偶联受体异源复合体更好地了解2AR/mGluR2复合体的结构和功能，并可能为治疗精神分裂症的新的药理学方法提供基础。与公共卫生相关：精神分裂症是一种慢性、衰弱的精神障碍，影响着美国约1%的人口，是我们社会第七昂贵的医疗疾病。我们发现了一种新的神经受体复合体，可以在小鼠身上诱导幻觉，并在精神分裂症的大脑中受到影响。神经感受器的结构特征将扩大我们对精神病分子基础的理解，并可能为开发治疗精神分裂症的新的、更有效的药物提供一条途径。