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Science 297 (5581): 615-620

Copyright © 2002 by the American Association for the Advancement of Science

Modulation of Postendocytic Sorting of G Protein-Coupled Receptors

Jennifer L. Whistler,1* Johan Enquist,2 Aaron Marley,3 Jamie Fong,1 Fredrik Gladher,2 Pamela Tsuruda,3 Stephen R. Murray,3 Mark von Zastrow3*

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.

1 Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, CA 94608, USA.
2 Program in Molecular Medicine, University of Lund, Sweden.
3 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: shooz2{at}itsa.ucsf.edu (J.L.W); zastrow{at}itsa.ucsf.edu (M.v.Z.)

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