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J. Biol. Chem., Vol. 280, Issue 10, 9528-9535, March 11, 2005

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-Arrestin Binding to the ₂-Adrenergic Receptor Requires Both Receptor Phosphorylation and Receptor Activation^*

Cornelius Krasel, Moritz Bünemann, Kristina Lorenz, and Martin J. Lohse

From the Institute for Pharmacology and Toxicology, Versbacher Strasse 9, D-97078 Würzburg, Germany

Homologous desensitization of ₂-adrenergic receptors has been shown to be mediated by phosphorylation of the agonist-stimulated receptor by G-protein-coupled receptor kinase 2 (GRK2) followed by binding of -arrestins to the phosphorylated receptor. Binding of -arrestin to the receptor is a prerequisite for subsequent receptor desensitization, internalization via clathrin-coated pits, and the initiation of alternative signaling pathways. In this study we have investigated the interactions between receptors and -arrestin2 in living cells using fluorescence resonance energy transfer. We show that (a) the initial kinetics of -arrestin2 binding to the receptor is limited by the kinetics of GRK2-mediated receptor phosphorylation; (b) repeated stimulation leads to the accumulation of GRK2-phosphorylated receptor, which can bind -arrestin2 very rapidly; and (c) the interaction of -arrestin2 with the receptor depends on the activation of the receptor by agonist because agonist withdrawal leads to swift dissociation of the receptor--arrestin2 complex. This fast agonist-controlled association and dissociation of -arrestins from prephosphorylated receptors should permit rapid control of receptor sensitivity in repeatedly stimulated cells such as neurons.

Received for publication, November 19, 2004 , and in revised form, December 9, 2004.

^* This work was supported by Sonderforschungsbereich 487 "Regulatory Membrane Proteins," by a Leibniz grant from the Deutsche Forschungsgemeinschaft, and by the Fonds der Chemischen Industrie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental movie S1.

To whom correspondence should be addressed. Tel.: 49-931-20148400; Fax: 49-931-20148411; E-mail: lohse{at}toxi.uni-wuerzburg.de.

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