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G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits

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dc.contributor.author Kossatz de Mello, Elk, 1977-
dc.contributor.author Diez Alarcia, Rebeca
dc.contributor.author Gaitonde, Supriya A.
dc.contributor.author Ramon Duaso, Carla, 1987-
dc.contributor.author Stepniewski, Tomasz Maciej, 1988-
dc.contributor.author Aranda García, David
dc.contributor.author Muneta Arrate, Itziar
dc.contributor.author Tepaz, Elodie
dc.contributor.author Saen-Oon, Suwipa
dc.contributor.author Soliva, Robert
dc.contributor.author Shahraki, Aida
dc.contributor.author Moreira, David
dc.contributor.author Brea, José
dc.contributor.author Loza, María I.
dc.contributor.author Torre Fornell, Rafael de la
dc.contributor.author Kolb, Peter
dc.contributor.author Bouvier, Michel
dc.contributor.author Meana, J. Javier
dc.contributor.author Robledo, Patricia, 1958-
dc.contributor.author Selent, Jana
dc.date.accessioned 2024-07-16T06:38:19Z
dc.date.available 2024-07-16T06:38:19Z
dc.date.issued 2024
dc.identifier.citation Kossatz 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/s41467-024-48196-2
dc.identifier.issn 2041-1723
dc.identifier.uri http://hdl.handle.net/10230/60760
dc.description.abstract 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-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.
dc.description.sponsorship This work was supported by the ERAnet NEURON consortium fund (funding was provided by CIHR NDD-161471 and FRQ-S 278647 for M.B., the German Federal Ministry of Education and Research under grant number 01EW1909 for P.K., as well as the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional number AC18/00030 for J.S. and P.R.). This work was further supported by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (PI18/00094) to J.S. and (PI18/00053) to P.R. We acknowledge grant support from Agencia Estatal de Investigación (PID2020-119428RB-I00; SAF2017-88126R), Basque Government (IT-1211/19, IT-1512/22 and KK-2019/00-49), Xunta de Galicia (ED431C 2022/20 and ED431G 2019/02) and European Regional Development Fund (ERDF). P.K. thanks the German Research Foundation DFG for Heisenberg Professorship KO4095/5-1. S.S.O. and R.S. thank the PTQ-17-09103 (Ayuda Torres Quevedo, Ministerio de Ciencia e Innovación), and BioExcel-2 (Grant Number 823830, Horizon2020). M.B. was in part supported by an operating grant (# PJT 183758) from the Canadian Institute for Health Research. I.M-A. was the recipient of a predoctoral fellowship from the Basque Government. The authors would like to thank the staff members of the Basque Institute of Legal Medicine for their cooperation in the study, especially to Dr. Benito Morentin. R.D-A., T.M.S, D.A.G., I.M.A., A.S., P.K. and J.S. are members of COST Action CA18133 “ERNEST”.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nat Commun. 2024 May 29;15(1):4307
dc.rights © 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/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-48196-2
dc.subject.keyword Computational biophysics
dc.subject.keyword G protein-coupled receptors
dc.subject.keyword Schizophrenia
dc.subject.keyword Target validation
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/823830
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119428RB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-88126-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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