title: Pharmacological profile of engineered 5-HT₄ receptors and identification of 5-HT₄ receptor-biased ligands.
abstract: G protein-coupled receptors (GPCRs) can activate simultaneously multiple signaling pathways upon agonist binding. The combined use of engineered GPCRs, such as the receptors activated solely by synthetic ligands (RASSLs), and of biased ligands that activate only one pathway at a time might help deciphering the physiological role of each G protein signaling. In order to find serotonin type 4 receptor (5-HT₄R) biased ligands, we analyzed the ability of several compounds to activate the Gs and G(q/11) pathways in COS-7 cells that transiently express wild type 5-HT₄R, the 5-HT₄R-D(100)A mutant (known also as 5-HT₄-RASSL, or Rs1) or the 5-HT₄R-T(104)A mutant, which modifies agonist-induced 5-HT₄R activation. This analysis allowed completing the pharmacological profile of the two mutant 5-HT₄Rs, but we did not find any biased ligand for the mutant receptors. Conversely, we identified the first biased agonists for wild type 5-HT₄R. Indeed, RS 67333 and prucalopride acted as partial agonists to induce cAMP accumulation, but as antagonists on inositol phosphate production. Moreover, they showed very different antagonist potencies that could be exploited to study the activation of the G(s) pathway, with or without concomitant block of G(q/11) signaling. This article is part of a Special Issue entitled Optogenetics (7th BRES).
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Gaven
authors.forename: Lucie P
authors.initials: LP
authors.lastname: Pellissier
authors.forename: Emilie
authors.initials: E
authors.lastname: Queffeulou
authors.forename: Maud
authors.initials: M
authors.lastname: Cochet
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Aline
authors.initials: A
authors.lastname: Dumuis
authors.forename: Sylvie
authors.initials: S
authors.lastname: Claeysen
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D009154:Mutation / Q000235:genetics; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics* / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D014162:Transfection
chemical_list: D007295:Inositol Phosphates; D008024:Ligands; D018490:Serotonin Agents; D044422:Receptors, Serotonin, 5-HT4; D000242:Cyclic AMP