Structure and function of GPCR heteromeric complexes in brain

重度抑郁症是一种精神疾病，约占世界人口的16%。目前 包括单胺药物疗法在内的现有干预措施需要数周至数月， 产生有益的效果。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，起效更快， 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-一种致幻5-羟色胺5-HT 2A受体（5-HT 2AR）激动剂， 抗抑郁作用的患者患有严重抑郁症。尽管有这些惊人的效果，一些 各种心理领域的改变，包括感官知觉和思维过程，排除了 在日常临床实践中常规使用裸盖菇素和其他致幻剂。G蛋白偶联受体 是细胞信号传导的关键介质。虽然被认为能够激活G蛋白的单体， 形式，许多研究揭示了它们可能与异源寡聚体结合，使变构串扰成为可能。 在受体原体之间。我们以前报道过5-HT 2AR和代谢型谷氨酸受体2， （mGluR 2）能够物理相互作用以形成GPCR复合物。此R 01授权的早期版本的结果 表明至少部分细胞信号和精神病样行为由致幻5- HT 2AR激动剂需要在小鼠额叶皮质中表达5-HT 2AR-mGluR 2异聚体。但 皮质5-HT 2AR-mGluR 2影响与致幻剂后抑郁相关的行为状态的能力 给药仍有待阐明。类似地，由于GPCR寡聚化的功能重要性仍然存在， 关于5-HT 2AR-mGluR 2的基本结构和信号传导特性的有争议的额外研究 复杂是需要的。我们公布的数据和这里提供的初步数据支持我们的工作。 假设家族间GPCR异聚化影响 5-HT 2AR和mGluR 2在活的哺乳动物细胞中。我们的数据也符合假设， 单剂量致幻5-HT 2AR激动剂诱导对缓解 与抑郁症相关的行为状态，这些治疗相关的表型需要表达 5-HT 2AR和mGluR 2作为GPCR异聚体在小鼠额叶皮质中的表达。这些数据为 独特的抗抑郁作用的分子机制的全面分析， 致幻剂，最终目标是开发更安全，更有效，非致幻性抑郁症 治疗策略。

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.