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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.
Here authors aim to understand the 5-HT2AR coupling signature in response to different signaling probes and their physiological impacts using computational modeling, in vitro and in vivo experiments, and analysis of human brain tissue.
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1 Hospital del Mar Research Institute, Integrative Pharmacology and Systems Neuroscience Research Group, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005)
2 University of the Basque Country/Euskal Herriko Unibertsitatea, Department of Pharmacology, Leioa, Spain (GRID:grid.11480.3c) (ISNI:0000 0001 2167 1098); Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Madrid, Spain (GRID:grid.469673.9) (ISNI:0000 0004 5901 7501); Instituto de Investigación Sanitaria Biobizkaia, Barakaldo, Spain (GRID:grid.469673.9)
3 Montréal, Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Québec, Canada (GRID:grid.459284.6) (ISNI:0000 0001 1410 5338)
4 IMIM-Hospital del Mar Medical Research Institute, Cell-type mechanisms in normal and pathological behaviour Research Group, Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005)
5 Hospital del Mar Research Institute, Research Programme on Biomedical Informatics (GRIB), Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); PARK InnovAARE, InterAx Biotech AG, Villigen, Switzerland (GRID:grid.20522.37)
6 Hospital del Mar Research Institute, Research Programme on Biomedical Informatics (GRIB), Barcelona, Spain (GRID:grid.20522.37) (ISNI:0000 0004 1767 9005); Pompeu Fabra University, Department of Medicine and Life Sciences, Barcelona, Spain (GRID:grid.5612.0) (ISNI:0000 0001 2172 2676)
7 University of the Basque Country/Euskal Herriko Unibertsitatea, Department of Pharmacology, Leioa, Spain (GRID:grid.11480.3c) (ISNI:0000 0001 2167 1098); Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Madrid, Spain (GRID:grid.469673.9) (ISNI:0000 0004 5901 7501)
8 NBD NOSTRUM BIODISCOVERY, Barcelona, Spain (GRID:grid.459284.6)
9 University of Marburg, Pharmaceutical Chemistry, Marburg, Germany (GRID:grid.10253.35) (ISNI:0000 0004 1936 9756)
10 University of Santiago de Compostela, Innopharma Drug Screening and Pharmacogenomics Platform. BioFarma research group. Center for Research in Molecular Medicine and Chronic Diseases (CiMUS). Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Santiago de Compostela, Spain (GRID:grid.11794.3a) (ISNI:0000000109410645); University Hospital of Santiago de Compostela (SERGAS), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain (GRID:grid.411048.8) (ISNI:0000 0000 8816 6945)
11 University of Marburg, Pharmaceutical Chemistry, Marburg, Germany (GRID:grid.10253.35) (ISNI:0000 0004 1936 9756); University of Santiago de Compostela, Innopharma Drug Screening and Pharmacogenomics Platform. BioFarma research group. Center for Research in Molecular Medicine and Chronic Diseases (CiMUS). Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Santiago de Compostela, Spain (GRID:grid.11794.3a) (ISNI:0000000109410645)