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

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.

Fig. 1.

Examples of G protein- and β-arrestin-mediated downstream signaling pathways on GPCRs. Upon agonist binding to GPCRs, both G proteins (Gα₁₂, Gα_q/11, Gα_i/o, Gα_s, 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 Gα_q can induce the mobilization of calcium from intracellular stores through activation of PLC/IP3. Gα_o signaling activates MEK/ERK pathway to mediate cell cycle progression. Gα_s 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.

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.