G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits
Elk Kossatz, Rebeca Dı́ez-Alarcia, Supriya A. Gaitonde, Carla Ramon‐Duaso, Tomasz Maciej Stępniewski, David Aranda-García, Itziar Muneta‐Arrate, Elodie Tepaz, Suwipa Saen‐oon, Robert Soliva, Aida Shahraki, David Moreira, José Brea, Marı́a Isabel Loza, Rafael de la Torre, Peter Kolb, Michel Bouvier, J. Javier Meana, Patricia Robledo, Jana Selent
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-HT 2A R), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT 2A R 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-HT 2A R and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by G αq protein activation, whereas psychosis-related behavior is modulated through G αi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.