title: Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy.
abstract: G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters, representing the largest group of therapeutic targets. Recent studies show that some GPCRs signal through both G protein and arrestin pathways in a ligand-specific manner. Ligands that direct signaling through a specific pathway are known as biased ligands. The arginine-vasopressin type 2 receptor (V2R), a prototypical peptide-activated GPCR, is an ideal model system to investigate the structural basis of biased signaling. Although the native hormone arginine-vasopressin leads to activation of both the stimulatory G protein (Gs) for the adenylyl cyclase and arrestin pathways, synthetic ligands exhibit highly biased signaling through either Gs alone or arrestin alone. We used purified V2R stabilized in neutral amphipols and developed fluorescence-based assays to investigate the structural basis of biased signaling for the V2R. Our studies demonstrate that the Gs-biased agonist stabilizes a conformation that is distinct from that stabilized by the arrestin-biased agonists. This study provides unique insights into the structural mechanisms of GPCR activation by biased ligands that may be relevant to the design of pathway-biased drugs.
authors.affiliation: Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Institut National de la Santé et de la Recherche Médicale U661, Université Montpellier 1, 34094 Montpellier Cedex 05, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Rahmeh
authors.forename: Marjorie
authors.initials: M
authors.lastname: Damian
authors.forename: Martin
authors.initials: M
authors.lastname: Cottet
authors.forename: Hélène
authors.initials: H
authors.lastname: Orcel
authors.forename: Christiane
authors.initials: C
authors.lastname: Mendre
authors.forename: Thierry
authors.initials: T
authors.lastname: Durroux
authors.forename: K Shivaji
authors.initials: KS
authors.lastname: Sharma
authors.forename: Grégory
authors.initials: G
authors.lastname: Durand
authors.forename: Bernard
authors.initials: B
authors.lastname: Pucci
authors.forename: Eric
authors.initials: E
authors.lastname: Trinquet
authors.forename: Jurriaan M
authors.initials: JM
authors.lastname: Zwier
authors.forename: Xavier
authors.initials: X
authors.lastname: Deupi
authors.forename: Patrick
authors.initials: P
authors.lastname: Bron
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Banères
authors.forename: Bernard
authors.initials: B
authors.lastname: Mouillac
authors.forename: Sébastien
authors.initials: S
authors.lastname: Granier
mesh_terms: D008024:Ligands; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence / Q000379:methods*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled