title: Phosphorylation barcoding as a mechanism of directing GPCR signaling.
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.
authors.affiliation: Cardiopulmonary Genomics Program, Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. sligg001@umaryland.edu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D054768:G-Protein-Coupled Receptor Kinases