Signaling arrestin scaffolds

LuttreU, L. M., Roudabush, F. L., Choy, E. W., Miller, W. E., Field, M. E., Pierce, K. L., et al. (2001). Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proceedings of the National Academy of Sciences of the United States ofAmerica, 98, 2449-2454. 

Schulte, G. (2010). International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors. Pharmacol Rev 62,632-67, ISSN 0031-6997 Schulte, G. Schambony, A. Bryja, V. (2010). beta-Arrestins - scaffolds and signalling elements essential for WNT/Frizzled signalling pathways Br Pharmacol 159, 1051-8, ISSN 0007-1188... 

As described in more detail below, agonist binding will lead to signaling as well as phosphorylation of Ser and Thr residues, especially, but also, in selected cases, Tyr residues located in intracellular loop-3 and in the C-terminal extension. This post-translational modification alters the affinity of the receptor for various intracellular proteins, including arrestin, which sterically prevents further G-protein binding and functions as an adaptor protein. Also, interaction with other types of scaffolding proteins such as PSD-95-like proteins, is influenced by the phosphorylation state of the receptor. 

Cyclic AMP is eventually eliminated by cAMP phosphodiesterase, and Gs turns itself off by hydrolysis of its bound GTP to GDP. When the epinephrine signal persists, j8-adrenergic receptor-specific protein kinase and arrestin 2 temporarily desensitize the receptor and cause it to move into intracellular vesicles. In some cases, arrestin also acts as a scaffold protein, bringing together protein components of a signaling pathway such as the MAPK cascade. 

Miller, W.E. and Lefkowitz, R.J. (2001). Expanding roles for P-arrestins as scaffolds and adaptors in GPCR signaling and trafficking. Curr. Opin. Cell Biol. 13, 139-145. 

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