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J. Biol. Chem., Vol. 282, Issue 5, 3095-3104, February 2, 2007

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A Novel Sorting Sequence in the ₂-Adrenergic Receptor Switches Recycling from Default to the Hrs-dependent Mechanism^*

From the Department of Psychiatry, University of California, San Francisco, California 94158

Plasma membrane recycling of G protein-coupled receptors can occur by at least two distinct mechanisms as follows: a "default" mechanism that occurs nonselectively, and a specifically sorted mechanism that requires the endosome-associated protein Hrs. In this study we have defined a sequence in the ₂-adrenergic receptor cytoplasmic tail that confers Hrs dependence on receptor recycling. This sequence resembles acidic dileucine class motifs found in other membrane proteins but is structurally and functionally distinct from previously identified sorting sequences. Mutation of the novel sorting sequence rendered plasma membrane recycling independent of Hrs and independent of a distal PDZ ligand required for Hrs-dependent recycling. We propose that the novel sorting sequence functions to "switch" endocytic trafficking between mechanistically distinct recycling modes, thereby explaining failure of the wild type ₂-adrenergic receptor to recycle efficiently by default.

Received for publication, June 6, 2006 , and in revised form, October 31, 2006.

^* This work was supported in part by grants from the National Institutes of Health. 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 a postdoctoral research fellowship from the American Heart Association, Western States Affiliate.

² To whom correspondence should be addressed: University of California, San Francisco, MC 2140, Genentech Hall, Rm. N212E, 600 16th St., San Francisco, CA 94158. Tel.: 415-476-7855; Fax: 415-514-0169; E-mail: zastrow{at}itsa.ucsf.edu.

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