Softskill Riview Artikel 3

Nama   : Sintia Widyo Wati
NPM    : 2A214304
Kelas   : 3EB24

The Diverse Roles of Arrestin Scaffolds in G Protein–Coupled Receptor Signaling

Yuri K. Peterson and Louis M. Luttrell

Martin C. Michel, ASSOCIATE EDITOR

Pharmacological Reviews July 2017, 69 (3) 256-297; DOI: https://doi.org/10.1124/pr.116.013367

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Abstract

The visual/β-arrestins, a small family of proteins originally described for their role in the desensitization and intracellular trafficking of G protein–coupled receptors (GPCRs), have emerged as key regulators of multiple signaling pathways. Evolutionarily related to a larger group of regulatory scaffolds that share a common arrestin fold, the visual/β-arrestins acquired the capacity to detect and bind activated GPCRs on the plasma membrane, which enables them to control GPCR desensitization, internalization, and intracellular trafficking. By acting as scaffolds that bind key pathway intermediates, visual/β-arrestins both influence the tonic level of pathway activity in cells and, in some cases, serve as ligand-regulated scaffolds for GPCR-mediated signaling. Growing evidence supports the physiologic and pathophysiologic roles of arrestins and underscores their potential as therapeutic targets. Circumventing arrestin-dependent GPCR desensitization may alleviate the problem of tachyphylaxis to drugs that target GPCRs, and find application in the management of chronic pain, asthma, and psychiatric illness. As signaling scaffolds, arrestins are also central regulators of pathways controlling cell growth, migration, and survival, suggesting that manipulating their scaffolding functions may be beneficial in inflammatory diseases, fibrosis, and cancer. In this review we examine the structure–function relationships that enable arrestins to perform their diverse roles, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners. We conclude with a discussion of arrestins as therapeutic targets and the settings in which manipulating arrestin function might be of clinical benefit.

Footnotes

This work was supported by National Institutes of Health [Grants R01 DK055524 (to L.M.L.) and R01 GM095497 (to L.M.L.)], Department of Veterans Affairs Merit Review Grant I01 BX003188 (to L.M.L.), and the Research Service of the Charleston, South Carolina, Veterans Affairs Medical Center. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.

sumber: http://pharmrev.aspetjournals.org/content/69/3/256