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

描述（由申请人提供）：现代精神分裂症研究的指导目标之一是建立从分子和细胞生物学到这种精神病性精神障碍临床症状的桥梁。几十年来，单胺类神经递质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改变联系起来。值得注意的是，氯氮平和其他非典型抗精神病药物对血清素5-HT2A受体（2AR）具有高亲和力，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疗效。我们发现了一种新的和意想不到的功能性脑2AR/mGluR2受体复合物，它可能统一抗血清素和谷氨酸能治疗精神分裂症。我们的研究结果基于体外、动物模型和死后的精神分裂症受试者的大脑，表明这种2AR/mGluR2复合体可能是精神分裂症的一些精神病症状的原因，并且它是这两种不同类型的抗精神病药物的直接靶点。为了了解2AR/mGluR2复合物在脑功能中的作用，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尖端的计算方法来研究相互作用界面上负责2AR/mGluR2复合物稳定和功能串扰的分子决定因素。在皮质原代培养和小鼠体内模型中，我们将研究依赖于2AR/mGluR2复合物功能的神经元信号传导和行为。这些研究的结果有可能提供对2AR/mGluR2复合物的结构和功能的更深入的了解，而不是目前任何G蛋白偶联受体异复合体，并可能为精神分裂症治疗的新药理学方法提供基础。

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.