Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. - Archive ouverte HAL Access content directly
Journal Articles Proceedings of the National Academy of Sciences of the United States of America Year : 2012

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

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Hélène Orcel
Christiane Mendre
  • Function : Author
  • PersonId : 863723
Thierry Durroux
Eric Trinquet
  • Function : Author
Patrick Bron
  • Function : Author
  • PersonId : 832529

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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Dates and versions

inserm-00713711 , version 1 (02-07-2012)

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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, 2012, 109 (17), pp.6733-8. ⟨10.1073/pnas.1201093109⟩. ⟨inserm-00713711⟩
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