Journal
SCIENCE SIGNALING
Volume 4, Issue 185, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2002331
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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 beta-arrestins, which partially quenches receptor coupling to G proteins. For some receptors, this GRK-mediated phosphorylation stimulates additional signaling through the scaffolding action of beta-arrestin. These downstream signals are configured by beta-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 beta-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 beta-arrestin explains the multidimensional nature of signaling in the superfamily and represents new opportunities for drug discovery.
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