Kossatz de Mello, Elk, 1977-Diez Alarcia, RebecaGaitonde, Supriya A.Ramon Duaso, Carla, 1987-Stepniewski, Tomasz Maciej, 1988-Aranda García, DavidMuneta Arrate, ItziarTepaz, ElodieSaen-Oon, SuwipaSoliva, RobertShahraki, AidaMoreira, DavidBrea, JoséLoza, María I.Torre Fornell, Rafael de laKolb, PeterBouvier, MichelMeana, J. JavierRobledo, Patricia, 1958-Selent, Jana2024-07-162024-07-162024Kossatz E, Diez-Alarcia R, Gaitonde SA, Ramon-Duaso C, Stepniewski TM, Aranda-Garcia D, et al. G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits. Nat Commun. 2024 May 29;15(1):4307. DOI: 10.1038/s41467-024-48196-22041-1723http://hdl.handle.net/10230/60760G 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-HT2AR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT2AR 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-HT2AR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by Gαq protein activation, whereas psychosis-related behavior is modulated through Gαi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.application/pdfeng© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-024-48196-2Computational biophysicsG protein-coupled receptorsSchizophreniaTarget validationinfo:eu-repo/semantics/openAccess