Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 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

Zuzana Bologna  1 , Jian-Peng Teoh  1 , Ahmed S Bayoumi  1 , Yaoliang Tang  1 , Il-Man Kim  1   2
Affiliations
Review

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

Zuzana Bologna et al. Biomol Ther (Seoul). .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Examples of G protein- and β-arrestin-mediated downstream signaling pathways on GPCRs. Upon agonist binding to GPCRs, both G proteins (Gα12, Gαq/11, Gαi/o, Gαs, Gβ and Gγ subunits) and β-arrestin are activated to mediate a variety of distinct downstream signaling pathways. Stimulation of Gβ subunit can activate PI3Kγ and Gγ subunit can activate PKD. Gα12 can activate Rho kinase signaling pathways and Gαq can induce the mobilization of calcium from intracellular stores through activation of PLC/IP3. Gαo signaling activates MEK/ERK pathway to mediate cell cycle progression. Gαs proteins promote AC-induced PKA activation. Phosphorylation of GPCRs by GRK results in the recruitment of β-arrestin, which in turn desensitizes G protein signaling, mediates receptor trafficking to endosomes, and activates β-arrestin-dependent signaling.
Fig. 2.
Fig. 2.
Carvedilol-mediated β-arrestin biased signaling on β1-adrenergic receptors in cardiomyocytes and hearts. Carvedilol selectively stimulates GRK5/6- and β-arrestin-dependent cardioprotective signaling without activating deleterious G protein signaling. Carvedilol-mediated GRK5/6 phosphorylation of β1-adrenergic receptors leads to β-arrestin1’s translocation into nucleus where β-arrestin1 interacts with a subset of primary miRs and components of the Drosha microprocessor complex. This results in an increased level of a subset of miRs, which act as cardioprotective miRs by repressing pro-apoptotic genes in cardiomyocytes and hearts.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ahn S, Kim J, Hara MR, Ren XR, Lefkowitz RJ. β-arrestin-2 mediates anti-apoptotic signaling through regulation of BAD phosphorylation. J Biol Chem. 2009;284:8855–8856. doi: 10.1074/jbc.M808463200. - DOI - PMC - PubMed
    1. Alonso N, Zappia CD, Cabrera M, Davio CA, Shayo C, Monczor F, Fernandez NC. Physiological implications of biased signaling at histamine H2 receptors. Front Pharmacol. 2015;6:45. doi: 10.3389/fphar.2015.00045. - DOI - PMC - PubMed
    1. Angers S, Salahpour A, Joly E, Hilairet S, Chelsky D, Dennis M, Bouvier M. Detection of β2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET) Proc Natl Acad Sci USA. 2000;97:3684–3689. - PMC - PubMed
    1. Aplin M, Christensen GL, Schneider M, Heydorn A, Gammeltoft S, Kjolbye AL, Sheikh SP, Hansen JL. The angiotensin type 1 receptor activates extracellular signal-regulated kinases 1 and 2 by G protein-dependent and -independent pathways in cardiac myocytes and Langendorff-perfused hearts. Basic Clin Pharmacol Toxicol. 2007;100:289–295. doi: 10.1111/j.1742-7843.2007.00063.x. - DOI - PubMed
    1. Aurora AB, Mahmoud AI, Luo X, Johnson BA, van Rooij E, Matsuzaki S, Humphries KM, Hill JA, Bassel-Duby R, Sadek HA, Olson EN. MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death. J Clin Invest. 2012;122:1222–1232. doi: 10.1172/JCI59327. - DOI - PMC - PubMed

LinkOut - more resources