Structure and function of GPCR heteromeric complexes in brain

脑内GPCR异聚复合物的结构和功能

• 批准号: 10252884
• 负责人: Javier González-Maeso
• 金额: $ 46.51万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252884
• 关键词: Affect; Agonist; Amber; Anabolism; Antidepressive Agents; Basic Science; Behavior; Behavioral; Biological Assay; Brain; Brain region; Cell surface; Cells; Chronic stress; Clinical; Clinical Research; Clinical Trials; Codon Nucleotides; Cognition; Complex; Coupled; Data; Data Set; Dendritic Spines; Disease remission; Dose; Endoplasmic Reticulum; Event; Family; Fluorescence Microscopy; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Grant; HTR2A gene; Hallucinogens; In Vitro; Individual; Intervention; Ketamine; Macromolecular Complexes; Major Depressive Disorder; Mammalian Cell; Maps; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Modeling; Molecular; Molecular Analysis; Moods; Morphology; Mus; NMDA receptor antagonist; Neurons; Pathway interactions; Patients; Peptides; Perception; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phenylalanine; Population; Positioning Attribute; Process; Property; Protomer; Psyche structure; Psychoses; Publishing; Reporting; Role; Sensory; Serotonin; Serotonin Receptor 5-HT2A; Signal Transduction; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Translational Research; Transmembrane Domain; Viral; antidepressant effect; base; cell type; clinical practice; density; frontal lobe; metabotropic glutamate receptor 2; monoamine; neural circuit; novel; receptor; receptor expression; recombinase-mediated cassette exchange; response; side effect; single molecule; stoichiometry; treatment strategy; unnatural amino acids

Major depressive disorder is a mental illness afflicting approximately 16% of the world population. Currently available interventions including monoamine-based pharmacotherapies require several weeks to months for beneficial effects to occur. In addition, these treatments are often accompanied by undesirable side effects. Therefore, there is an urgent need for better antidepressant medications, with a faster onset of action, which will also be effective in patients who do not respond to classical antidepressants. Recent clinical findings suggest that psilocybin – a hallucinogenic serotonin 5-HT2A receptor (5-HT2AR) agonist, exerts fast-acting and long-lasting antidepressant actions in patients suffering from major depression. Despite these striking effects, a number of alterations in various mental domains, including sensory perception and thought processes, precludes the routine use of psilocybin and other hallucinogens in daily clinical practice. G protein-coupled receptors (GPCRs) are critical mediators of cell signaling. Although recognized as capable of activating G proteins in a monomeric form, numerous studies reveal their possible association into hetero-oligomers, enabling allosteric crosstalk between receptor protomers. We previously reported that 5-HT2AR and metabotropic glutamate receptor 2 (mGluR2) are able to interact physically to form a GPCR complex. Results from earlier versions of this R01 grant showed that at least part of the cellular signaling and psychosis-like behaviors induced by hallucinogenic 5- HT2AR agonists require expression of the 5-HT2AR-mGluR2 heteromer in the mouse frontal cortex. However, the ability of cortical 5-HT2AR-mGluR2 to affect behavioral states associated with depression upon hallucinogen administration remains to be elucidated. Similarly, as the functional importance of GPCR oligomerization remains controversial, additional studies related to basic structural and signaling properties of the 5-HT2AR-mGluR2 complex are needed. Our published data and the preliminary data presented here support our working hypothesis that inter-family GPCR heteromerization affects structure, sub-cellular localization and function of both 5-HT2AR and mGluR2 in living mammalian cells. Our data are also consonant with the hypothesis that a single dose of hallucinogenic 5-HT2AR agonists induces fast-acting and long-lasting effects on remission of behavioral states associated with depression, and that these therapeutic-related phenotypes require expression of 5-HT2AR and mGluR2 as a GPCR heteromer in the frontal cortex of mice. These data set the stage for a uniquely comprehensive analysis of the molecular mechanism underlying the antidepressant effects of hallucinogens, with the ultimate goal of developing safer, more effective, and non-hallucinogenic depression treatment strategies.

严重抑郁障碍是一种精神疾病，困扰着大约16%的世界人口。目前 可用的干预措施，包括基于单胺的药物疗法，需要几周到几个月的时间 将会产生有益的影响。此外，这些治疗往往伴随着不良的副作用。 因此，迫切需要更好的抗抑郁药物，以更快的起效，这将 对经典抗抑郁药无效的患者也有效。最近的临床研究结果表明 裸盖菇素是一种致幻的5-HT2A型受体(5-HT2AR)激动剂，作用迅速且持久 重度抑郁症患者的抗抑郁作用。尽管有这些惊人的影响，但一些 不同心智领域的改变，包括感觉和思维过程，排除了 在日常临床实践中常规使用裸盖菇素和其他迷幻剂。G蛋白偶联受体 是细胞信号的关键媒介。尽管被认为能够激活单体中的G蛋白 形式，许多研究揭示它们可能结合成杂化低聚物，使得变构串扰成为可能 在受体原体间。我们先前报道了5-HT2AR和代谢型谷氨酸受体2 (MGluR2)能够物理上相互作用形成GPCR复合体。此R01授权的早期版本的结果 研究表明，致幻剂5-羟色胺诱导的细胞信号和精神病样行为至少有一部分 HT2AR激动剂需要在小鼠额叶皮质表达5-HT2AR-mGluR2异构体。然而， 皮质5-HT2AR-mGluR2对致幻剂引起的抑郁相关行为状态的影响 具体的管理方法有待阐明。同样，由于GPCR寡聚的功能重要性仍然存在 与5-HT2AR-mGluR2的基本结构和信号特性相关的有争议的补充研究 都是需要的。我们公布的数据和这里提供的初步数据支持我们的工作 家族间gpr异构化影响细胞结构、亚细胞定位和功能的假说 5-HT2AR和mGluR2在活的哺乳动物细胞中均有表达。我们的数据也与假设一致，即 单剂量致幻5-HT2AR激动剂对慢性阻塞性肺疾病缓解的快速和持久影响 与抑郁症相关的行为状态，以及这些与治疗相关的表型需要表达 5-HT2AR和mGluR2作为GPCR异构体在小鼠额叶皮质中的表达。这些数据为 独一无二的全面分析抗抑郁作用的分子机制 致幻剂，最终目标是发展更安全、更有效和非致幻性抑郁症 治疗策略。