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J. Biol. Chem., Vol. 282, Issue 40, 29178-29185, October 5, 2007

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Changes in G Protein-coupled Receptor Sorting Protein Affinity Regulate Postendocytic Targeting of G Protein-coupled Receptors^*

Dawn Thompson, Margareta Pusch, and Jennifer L. Whistler¹

From the Ernest Gallo Clinic and Research Center and the Department of Neurology, University of California, San Francisco, Emeryville, California 94608

After activation, most G protein-coupled receptors (GPCRs) are regulated by a cascade of events involving desensitization and endocytosis. Internalized receptors can then be recycled to the plasma membrane, retained in an endosomal compartment, or targeted for degradation. The GPCR-associated sorting protein, GASP, has been shown to preferentially sort a number of native GPCRs to the lysosome for degradation after endocytosis. Here we show that a mutant ₂ adrenergic receptor and a mutant µ opioid receptor that have previously been described as lacking "recycling signals" due to mutations in their C termini in fact bind to GASP and are targeted for degradation. We also show that a mutant dopamine D1 receptor, which has likewise been described as lacking a recycling signal, does not bind to GASP and is therefore not targeted for degradation. Together, these results indicate that alteration of receptors in their C termini can expose determinants with affinity for GASP binding and consequently target receptors for degradation.

Received for publication, May 16, 2007 , and in revised form, July 11, 2007.

^* This work was supported by the National Institute of Mental Health Grant MH068442, the National Institute on Drug Abuse Grant DA015232 and funds provided by the State of California for medical research on alcohol and substance abuse through the University of California San Francisco (to J. L. W.) and a National Alliance for Research on Schizophrenia and Depression Young Investigator award (to D. T.). 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 To whom correspondence should be addressed: Ernest Gallo Clinic and Research Center, Dept. of Neurology, University of California, San Francisco, 5858 Horton St., Suite 200, Emeryville, CA 94608. Tel.: 510-985-3127; Fax: 510-985-3101; E-mail: Jennifer.whistler{at}ucsf.edu.

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