RT Journal Article
T1 G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits
A1 Kossatz, Elk
A1 Díez Alarcia, Rebeca
A1 Gaitonde, Supriya A.
A1 Ramón Duaso, Carla
A1 Stepniewski, Tomasz Maciej
A1 Aranda García, David
A1 Muneta Arrate, Itziar
A1 Tepaz, Elodie
A1 Saen Oon, Suwipa
A1 Soliva, Robert
A1 Shahraki, Aida
A1 Moreira, David
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
A1 Torre, Rafael de la
A1 Kolb, Peter
A1 Bouvier, Michel
A1 Meana, J. Javier
A1 Robledo, Patricia
A1 Selent, Jana
K1 Computational biophysics
K1 G protein-coupled receptors
K1 Schizophrenia
K1 Target validation
AB 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
PB Nature Communications
YR 2024
FD 2024-05-29
LK https://hdl.handle.net/10347/45289
UL https://hdl.handle.net/10347/45289
LA eng
NO Kossatz, E., Diez-Alarcia, R., Gaitonde, S.A. et al. G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits. Nat Commun 15, 4307 (2024). https://doi.org/10.1038/s41467-024-48196-2
NO 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”
DS Minerva
RD 24 abr 2026