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.

Time-gated detection of protein-protein interactions with transcriptional readout

“…Future applications of PPI-FLARE might include examination of GPCR "biased" signaling 38 . Here, we used only arrestin-TEVp with our GPCR panel, but it should be possible to replace the arrestin gene with Gi, Gs, or Gq and compare intensities and timecourses of G protein versus arrestin recruitment to GPCRs in response to various ligands.…”

Biased Receptor Signaling in Drug Discovery

“…This has led researchers to postulate that nonspecific endothelin A receptor blockade appears to inhibit both the oncogenic and tumor-suppressive effects to negate a beneficial effect. This further suggests that a biased antagonist of the Ga q and/or b-arrestin effects of endothelin 1 would be beneficial (Bologna et al, 2017).…”

Novel M2‐selective, Gi‐biased agonists of muscarinic acetylcholine receptors

“…Two of these compounds exclusively inhibited synthesis of cAMP (through activation of the G i/o signalling pathway) and did not stimulate accumulation of inositol phosphates (IP X ; G q pathway), either in a heterologous expression system or in digests of tissues and primary cultures. Although G i versus β‐arrestin‐biased agonists have been reported (e.g., at opioid receptors, DeWire et al, ), G i/o bias at the G‐protein level has not been reported so far (Bologna, Teoh, Bayoumi, Tang, & Kim, ). Molecular modelling confirmed the absence of hydrogen bonding of the novel agonists with Asn 6.52 in the sixth transmembrane helix and the existence of agonist‐specific conformations induced by the novel agonists.…”