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J. Biol. Chem., Vol. 283, Issue 46, 31840-31848, November 14, 2008

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Dual Role of the β₂-Adrenergic Receptor C Terminus for the Binding of β-Arrestin and Receptor Internalization^*

Cornelius Krasel¹², Ulrike Zabel, Kristina Lorenz, Susanne Reiner, Suleiman Al-Sabah¹, and Martin J. Lohse

From the Institute of Pharmacology and Toxicology, Versbacher Strasse 9, D-97078 Wuerzburg, Germany and the School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AJ, United Kingdom

Homologous desensitization of β₂-adrenergic and other G-protein-coupled receptors is a two-step process. After phosphorylation of agonist-occupied receptors by G-protein-coupled receptor kinases, they bind β-arrestins, which triggers desensitization and internalization of the receptors. Because it is not known which regions of the receptor are recognized by β-arrestins, we have investigated β-arrestin interaction and internalization of a set of mutants of the human β₂-adrenergic receptor. Mutation of the four serine/threonine residues between residues 355 and 364 led to the loss of agonist-induced receptor-β-arrestin2 interaction as revealed by fluorescence resonance energy transfer (FRET), translocation of β-arrestin2 to the plasma membrane, and receptor internalization. Mutation of all seven serine/threonine residues distal to residue 381 did not affect agonist-induced receptor internalization and β-arrestin2 translocation. A β₂-adrenergic receptor truncated distal to residue 381 interacted normally with β-arrestin2, whereas its ability to internalize in an agonist-dependent manner was compromised. A similar impairment of internalization was observed when only the last eight residues of the C terminus were deleted. Our experiments show that the C terminus distal to residue 381 does not affect the initial interaction between receptor and β-arrestin, but its last eight amino acids facilitate receptor internalization in concert with β-arrestin2.

Received for publication, August 6, 2008 , and in revised form, September 16, 2008.

^* This work was supported in part by SFB487 "Regulatory Membrane Proteins," by a Leibniz grant from the DFG, 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.

¹ Supported by New Investigator Grant BB/D012902/1 from the Biotechnology and Biological Sciences Research Council.

² To whom correspondence should be addressed: School of Pharmacy, Whiteknights, P. O. Box 228, Reading RG6 6AJ, United Kingdom. E-mail: c.krasel{at}reading.ac.uk.

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