Recycling of the mu opioid receptor to the plasma membrane after endocytosis promotes rapid resensitization of signal transduction, whereas targeting of the delta opioid receptor (DOR) to lysosomes causes proteolytic down-regulation. We identified a protein that binds preferentially to the cytoplasmic tail of the DOR as a candidate heterotrimeric GTP-binding protein (G protein)–coupled receptor-associated sorting protein (GASP). Disruption of the DOR-GASP interaction through receptor mutation or overexpression of a dominant negative fragment of GASP inhibited receptor trafficking to lysosomes and promoted recycling. The GASP family of proteins may modulate lysosomal sorting and functional down-regulation of a variety of G protein–coupled receptors.

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We thank P. Chu for expert assistance in carrying out the yeast two-hybrid screen; U. Klein for valuable advice on the interaction cloning strategy and for performing initial GST binding assays; P. Tsao for insightful discussion and assistance in early studies of the GASP interaction; G. Vargas for providing the GST-D4 tail construct; and H. Bourne, H. Deacon, R. Edwards, A. Finn, R. Kelly, D. Ron, and M. Waldhoer for helpful discussion and critical reading of the manuscript. Supported by research grants from NIH (M.v.Z.) and funds provided by the state of California for medical research on alcohol and substance abuse (J.L.W.). J.L.W. is supported by a NARSAD young investigator award from the Staglin family and received an individual NRSA from NIH.
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Volume 297 | Issue 5581
26 July 2002

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Received: 26 April 2002
Accepted: 13 June 2002
Published in print: 26 July 2002


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Jennifer L. Whistler*
Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, CA 94608, USA.
Johan Enquist
Program in Molecular Medicine, University of Lund, Sweden.
Aaron Marley
Program in Cell Biology, Department of Psychiatry and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
Jamie Fong
Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, CA 94608, USA.
Fredrik Gladher
Program in Molecular Medicine, University of Lund, Sweden.
Pamela Tsuruda
Program in Cell Biology, Department of Psychiatry and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
Stephen R. Murray
Program in Cell Biology, Department of Psychiatry and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
Mark von Zastrow*
Program in Cell Biology, Department of Psychiatry and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.


To whom correspondence should be addressed. E-mail: [email protected] (J.L.W); [email protected] (M.v.Z.)

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