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Abstract
A unifying mechanism by which G protein–coupled receptors (GPCRs) signal in cell type–dependent and G protein–independent ways has developed over the past decade. GPCR kinases (GRKs) are mediators of homologous desensitization: GRK phosphorylation of the receptors leads to the subsequent binding of β-arrestins, which partially quenches receptor coupling to G proteins. For some receptors, this GRK-mediated phosphorylation stimulates additional signaling through the scaffolding action of β-arrestin. These downstream signals are configured by β-arrestin conformation, which is dictated by the GRK phosphoacceptors on the receptors in a barcode-like fashion. Furthermore, each of the GRKs can potentially phosphorylate different serine and threonine residues on a given receptor, and the phosphorylation pattern can be biased by the receptor conformation established by bound ligand. Finally, the arrangement of potential GRK phosphorylation sites—and thus the conformation of β-arrestin and its effect on downstream signaling—can differ substantially between even closely related GPCRs stimulated by the same agonist. The diversity of the barcoding to flexible β-arrestin explains the multidimensional nature of signaling in the superfamily and represents new opportunities for drug discovery.
