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Biomol Ther (Seoul). 2017 Jan 1;25(1):12-25. doi: 10.4062/biomolther.2016.165.

Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology.

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  • 1Vascular Biology Center, Medical College of Georgia, Augusta University, GA 30912, USA.
  • 2Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, GA 30912, USA.

Abstract

G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.

KEYWORDS:

G protein; G protein-coupled receptor; biased signaling; β-arrestin

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