Integrative Pharmacology and Systems Neuroscience Research Group, Hospital del Mar Research Institute, Barcelona, Spain.
Department of Pharmacology, University of the Basque Country/Euskal Herriko Unibertsitatea, Leioa, Bizkaia, Spain.
Nat Commun. 2024 May 29;15(1):4307. doi: 10.1038/s41467-024-48196-2.
G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HTR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HTR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HTR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by G protein activation, whereas psychosis-related behavior is modulated through G stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.
G 蛋白偶联受体（GPCRs）是一种复杂的信号转导机器，能够在激活后同时引发多种细胞内信号通路。对于特定的治疗应用，完全（不）激活所有通路可能会适得其反。这就是 5-羟色胺 2A 受体（5-HTR）的情况，它是治疗精神分裂症的重要靶点。在这项研究中，我们通过结合计算建模、体外和体内实验以及人类死后大脑研究，阐明了不同信号探针激活 5-HTR 时的复杂偶联特征及其生理后果。我们展示了内源性激动剂 5-羟色胺的化学修饰如何显著影响 5-HTR 的 G 蛋白偶联谱以及相关的行为反应。重要的是，在这些反应中，我们证明记忆缺陷受 G 蛋白激活调节，而与精神病相关的行为则通过 G 刺激调节。这些发现强调了 GPCR 药理学和生理学的复杂性，并为设计治疗精神分裂症的改进疗法开辟了道路。
