Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy.

Rita Rahmeh 1 Marjorie Damian 2 Martin Cottet 1 Hélène Orcel 1 Christiane Mendre 1 Thierry Durroux 1 K Shivaji Sharma 2, 3 Grégory Durand 2, 3 Bernard Pucci 2, 3 Eric Trinquet 4 Jurriaan Zwier 5, 4 Xavier Deupi 6 Patrick Bron 7 Jean-Louis Banères 2 Bernard Mouillac 1, * Sébastien Granier 1
* Corresponding author
1 IGF - Institut de Génomique Fonctionnelle
2 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
3 Equipe Chimie Bioorganique et Systèmes Amphiphiles
4 Cisbio Bioassays
5 Institute of Molecular Chemistry
6 Condensed Matter Theory Group and Laboratory of Biomolecular Research
7 CBS - Centre de Biochimie Structurale [Montpellier]
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.
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Submitted on : Monday, July 2, 2012 - 2:11:17 PM
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CNRS | UNIV-AVIGNON | INC-CNRS | CHIMIE | BS | UNIV-MONTPELLIER

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Rita Rahmeh, Marjorie Damian, Martin Cottet, Hélène Orcel, Christiane Mendre, et al.. Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy.. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2012, 109 (17), pp.6733-8. ⟨10.1073/pnas.1201093109⟩. ⟨inserm-00713711⟩

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