Progress in molecular biology and translational science
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The discovery that, in addition to mediating G protein-coupled receptor (GPCR) desensitization and endocytosis, arrestins bind to diverse catalytically active nonreceptor proteins and act as ligand-regulated signaling scaffolds led to a paradigm shift in the study of GPCR signal transduction. Research over the past decade has solidified the concept that arrestins confer novel GPCR-signaling capacity by recruiting protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into receptor-based multiprotein "signalsome" complexes. ⋯ While many arrestin-bound kinases and phosphatases are involved in the control of cytoskeletal rearrangement, vesicle endocytosis, exocytosis, and cell migration, other signals reach into the nucleus, affecting cell proliferation, apoptosis, and survival. Indeed, the kinase/phosphatase network regulated by arrestins may be fully as diverse as that regulated by heterotrimeric G proteins.
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Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) efficacy, coupled with the phenomenon of orthosteric ligand "bias," offers the prospect of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. As the best-studied non-G protein effectors, arrestins have been shown to mediate a wide range of GPCR signals, and arrestin pathway-selective ligands have been identified for several receptors. ⋯ Yet, when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. While some widely conserved arrestin-regulated biological processes are becoming apparent, what is lacking at present is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will aid drug discovery programs in identifying "biased" ligands with the desired biological effects.