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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.

SUBMITTER: Rahmeh R 

PROVIDER: S-EPMC3340029 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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

Rahmeh Rita R   Damian Marjorie M   Cottet Martin M   Orcel Hélène H   Mendre Christiane C   Durroux Thierry T   Sharma K Shivaji KS   Durand Grégory G   Pucci Bernard B   Trinquet Eric E   Zwier Jurriaan M JM   Deupi Xavier X   Bron Patrick P   Banères Jean-Louis JL   Mouillac Bernard B   Granier Sébastien S  

Proceedings of the National Academy of Sciences of the United States of America 20120409 17


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 mo  ...[more]

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