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

Elk Kossatz, Rebeca Diez-Alarcia, Supriya A. Gaitonde, Carla Ramon-Duaso, Tomasz Maciej Stepniewski, David Aranda-Garcia, Itziar Muneta-Arrate, Elodie Tepaz, Suwipa Saen-Oon, Robert Soliva, Aida Shahraki, David Moreira, Jose Brea, Maria Isabel Loza, Rafael de la Torre, Peter Kolb, Michel Bouvier, J. Javier Meana, Patricia Robledo () and Jana Selent ()
Additional contact information
Elk Kossatz: Hospital del Mar Research Institute
Rebeca Diez-Alarcia: University of the Basque Country/Euskal Herriko Unibertsitatea
Supriya A. Gaitonde: Montréal
Carla Ramon-Duaso: IMIM-Hospital del Mar Medical Research Institute
Tomasz Maciej Stepniewski: Hospital del Mar Research Institute
David Aranda-Garcia: Hospital del Mar Research Institute
Itziar Muneta-Arrate: University of the Basque Country/Euskal Herriko Unibertsitatea
Elodie Tepaz: Montréal
Suwipa Saen-Oon: NBD NOSTRUM BIODISCOVERY
Robert Soliva: NBD NOSTRUM BIODISCOVERY
Aida Shahraki: University of Marburg
David Moreira: University of Santiago de Compostela
Jose Brea: University of Marburg
Maria Isabel Loza: University of Santiago de Compostela
Rafael de la Torre: Hospital del Mar Research Institute
Peter Kolb: University of Marburg
Michel Bouvier: Montréal
J. Javier Meana: University of the Basque Country/Euskal Herriko Unibertsitatea
Patricia Robledo: Hospital del Mar Research Institute
Jana Selent: Hospital del Mar Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48196-2

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