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Originally published In Press as doi:10.1074/jbc.M209532200 on January 13, 2003

J. Biol. Chem., Vol. 278, Issue 13, 11623-11632, March 28, 2003
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The Nature of the Arrestin·Receptor Complex Determines the Ultimate Fate of the Internalized Receptor*

Ling Pan, Eugenia V. Gurevich, and Vsevolod V. GurevichDagger

From the Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232

The vast majority of G protein-coupled receptors are desensitized by a uniform two-step mechanism: phosphorylation of an active receptor followed by arrestin binding. The arrestin·receptor complex is then internalized. Internalized receptor can be recycled back to the plasma membrane (resensitization) or targeted to lysosomes for degradation (down-regulation). The intracellular compartment where this choice is made and the molecular mechanisms involved are largely unknown. Here we used two arrestin2 mutants that bind with high affinity to phosphorylated and unphosphorylated agonist-activated beta 2-adrenergic receptor to manipulate the receptor-arrestin interface. We found that mutants support rapid internalization of beta 2-adrenergic receptor similar to wild type arrestin2. At the same time, phosphorylation-independent arrestin2 mutants facilitate receptor recycling and sharply reduce the rate of receptor loss, effectively protecting beta 2-adrenergic receptor from down-regulation even after very long (up to 24 h) agonist exposure. Phosphorylation-independent arrestin2 mutants dramatically reduce receptor phosphorylation in response to an agonist both in vitro and in cells. Interestingly, co-expression of high levels of beta -adrenergic receptor kinase restores receptor down-regulation in the presence of mutants to the levels observed with wild type arrestin2. Our data suggest that unphosphorylated receptor internalized in complex with mutant arrestins recycles faster than phosphoreceptor and is less likely to get degraded. Thus, targeted manipulation of the characteristics of an arrestin protein that binds to a G protein-coupled receptors can dramatically change receptor trafficking and its ultimate fate in a cell.

* This work was supported in part by NIH Grants EY11500 and GM63097 (to V. V. G.) and MH62651 (to E. V. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology, Vanderbilt University School of Medicine, RRB, Rm. 454, Nashville, TN 37232. Tel.: 615-322-7070; E-mail: Vsevolod.Gurevich@mcmail.vanderbilt.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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