Phosphorylation Barcoding as a Mechanism of Directing GPCR Signaling

Stephen B. Liggett^*

Cardiopulmonary Genomics Program, Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

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.

* Corresponding author. E-mail, sligg001{at}umaryland.edu

The editors suggest the following Related Resources on Science sites:

In Science Signaling

RESEARCH ARTICLES
Cell Biology
Distinct Phosphorylation Sites on the β₂-Adrenergic Receptor Establish a Barcode That Encodes Differential Functions of β-Arrestin

Kelly N. Nobles, Kunhong Xiao, Seungkirl Ahn, Arun K. Shukla, Christopher M. Lam, Sudarshan Rajagopal, Ryan T. Strachan, Teng-Yi Huang, Erin A. Bressler, Makoto R. Hara, Sudha K. Shenoy, Steven P. Gygi, and Robert J. Lefkowitz (9 August 2011)
Sci. Signal. 4 (185), ra51. [DOI: 10.1126/scisignal.2001707]
 |  Editor's Summary »  |  Abstract »  |  Full Text »  |  PDF »  |  Supplementary Materials »

EDITORIAL GUIDES
Receptors
Focus Issue: Cracking the G Protein–Coupled Receptor Code

Nancy R. Gough (9 August 2011)
Sci. Signal. 4 (185), eg7. [DOI: 10.1126/scisignal.2002388]
 |  Abstract »  |  Full Text »  |  PDF »

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES: