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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} (J.L.W); zastrow{at} (M.v.Z.)

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J Mol Cell Biol 5, 250-265
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N. Audet, I. Charfi, O. Mnie-Filali, M. Amraei, A.-J. Chabot-Dore, M. Millecamps, L. S. Stone, and G. Pineyro (2012)
J. Neurosci. 32, 4827-4840
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. N. Hislop, A. G. Henry, and M. von Zastrow (2011)
J. Biol. Chem. 286, 40193-40204
   Abstract »    Full Text »    PDF »
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L. Milan-Lobo and J. L. Whistler (2011)
J. Pharmacol. Exp. Ther. 337, 868-875
   Abstract »    Full Text »    PDF »
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K. S. Kluetzman, R. M. Thomas, C. A. Nechamen, and J. A. Dias (2011)
Biol Reprod 84, 1154-1163
   Abstract »    Full Text »    PDF »
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C. Sanden, S. Broselid, L. Cornmark, K. Andersson, J. Daszkiewicz-Nilsson, U. E. A. Martensson, B. Olde, and L. M. F. Leeb-Lundberg (2011)
Mol. Pharmacol. 79, 400-410
   Abstract »    Full Text »    PDF »
Dopamine D3 Receptors Are Down-regulated following Heterologous Endocytosis by a Specific Interaction with G Protein-coupled Receptor-associated Sorting Protein-1.
D. Thompson and J. L. Whistler (2011)
J. Biol. Chem. 286, 1598-1608
   Abstract »    Full Text »    PDF »
Ligand-Directed Trafficking of the {delta}-Opioid Receptor In Vivo: Two Paths Toward Analgesic Tolerance.
A. A. A. Pradhan, W. Walwyn, C. Nozaki, D. Filliol, E. Erbs, A. Matifas, C. Evans, and B. L. Kieffer (2010)
J. Neurosci. 30, 16459-16468
   Abstract »    Full Text »    PDF »
Morphine-like Opiates Selectively Antagonize Receptor-Arrestin Interactions.
P. Molinari, V. Vezzi, M. Sbraccia, C. Gro, D. Riitano, C. Ambrosio, I. Casella, and T. Costa (2010)
J. Biol. Chem. 285, 12522-12535
   Abstract »    Full Text »    PDF »
Nerve Growth Factor-Regulated Emergence of Functional {delta}-Opioid Receptors.
B. Bie, Z. Zhang, Y. Q. Cai, W. Zhu, Y. Zhang, J. Dai, C. J. Lowenstein, E. J. Weinman, and Z. Z. Pan (2010)
J. Neurosci. 30, 5617-5628
   Abstract »    Full Text »    PDF »
Phosphorylation of Protease-activated Receptor-2 Differentially Regulates Desensitization and Internalization.
T. K. Ricks and J. Trejo (2009)
J. Biol. Chem. 284, 34444-34457
   Abstract »    Full Text »    PDF »
A Coated Vesicle-associated Kinase of 104 kDa (CVAK104) Induces Lysosomal Degradation of Frizzled 5 (Fzd5).
T. Terabayashi, Y. Funato, M. Fukuda, and H. Miki (2009)
J. Biol. Chem. 284, 26716-26724
   Abstract »    Full Text »    PDF »
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J. N. Hislop, A. G. Henry, A. Marchese, and M. von Zastrow (2009)
J. Biol. Chem. 284, 19361-19370
   Abstract »    Full Text »    PDF »
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Y. Namkung, C. Dipace, J. A. Javitch, and D. R. Sibley (2009)
J. Biol. Chem. 284, 15038-15051
   Abstract »    Full Text »    PDF »
Helix 8 of leukotriene B4 type-2 receptor is required for the folding to pass the quality control in the endoplasmic reticulum.
D. Yasuda, T. Okuno, T. Yokomizo, T. Hori, N. Hirota, T. Hashidate, M. Miyano, T. Shimizu, and M. Nakamura (2009)
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   Abstract »    Full Text »    PDF »
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A. Garcia-Regalado, M. L. Guzman-Hernandez, I. Ramirez-Rangel, E. Robles-Molina, T. Balla, J. Vazquez-Prado, and G. Reyes-Cruz (2008)
Mol. Biol. Cell 19, 4188-4200
   Abstract »    Full Text »    PDF »
Kinin B2 Receptor-Mediated Bradykinin Internalization and Metalloendopeptidase EP24.15-Dependent Intracellular Bradykinin Degradation.
C. Sanden, J. Enquist, S. H. Bengtson, H. Herwald, and L. M. F. Leeb-Lundberg (2008)
J. Pharmacol. Exp. Ther. 326, 24-32
   Abstract »    Full Text »    PDF »
Physiology of the Prion Protein.
R. Linden, V. R. Martins, M. A. M. Prado, M. Cammarota, I. Izquierdo, and R. R. Brentani (2008)
Physiol Rev 88, 673-728
   Abstract »    Full Text »    PDF »
Agonist-Promoted Lys63-Linked Polyubiquitination of the Human {kappa}-Opioid Receptor Is Involved in Receptor Down-Regulation.
J.-G. Li, D. S. Haines, and L.-Y. Liu-Chen (2008)
Mol. Pharmacol. 73, 1319-1330
   Abstract »    Full Text »    PDF »
Identification of a Postendocytic Sorting Sequence in CCR5.
M. Delhaye, A. Gravot, D. Ayinde, F. Niedergang, M. Alizon, and A. Brelot (2007)
Mol. Pharmacol. 72, 1497-1507
   Abstract »    Full Text »    PDF »
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D. Thompson, M. Pusch, and J. L. Whistler (2007)
J. Biol. Chem. 282, 29178-29185
   Abstract »    Full Text »    PDF »
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D.-F. Wu, T. Koch, Y.-J. Liang, R. Stumm, S. Schulz, H. Schroder, and V. Hollt (2007)
J. Biol. Chem. 282, 22239-22247
   Abstract »    Full Text »    PDF »
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X. Yi, R. Bouley, H. Y. Lin, S. Bechoua, T.-x. Sun, E. del Re, T. Shioda, M. K. Raychowdhury, H. A. J. Lu, A. B. Abou-Samra, et al. (2007)
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   Abstract »    Full Text »    PDF »
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A. Tappe-Theodor, N. Agarwal, I. Katona, T. Rubino, L. Martini, J. Swiercz, K. Mackie, H. Monyer, D. Parolaro, J. Whistler, et al. (2007)
J. Neurosci. 27, 4165-4177
   Abstract »    Full Text »    PDF »
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L. Martini, M. Waldhoer, M. Pusch, V. Kharazia, J. Fong, J. H. Lee, C. Freissmuth, and J. L. Whistler (2007)
FASEB J 21, 802-811
   Abstract »    Full Text »    PDF »
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B. L. Sanchez-Laorden, C. Jimenez-Cervantes, and J. C. Garcia-Borron (2007)
J. Biol. Chem. 282, 3241-3251
   Abstract »    Full Text »    PDF »
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J. Enquist, C. Skroder, J. L. Whistler, and L.M. F. Leeb-Lundberg (2007)
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   Abstract »    Full Text »    PDF »
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L. A. Gardner, S. J. Tavalin, A. S. Goehring, J. D. Scott, and S. W. Bahouth (2006)
J. Biol. Chem. 281, 33537-33553
   Abstract »    Full Text »    PDF »
Trafficking of G Protein-Coupled Receptors.
M. T. Drake, S. K. Shenoy, and R. J. Lefkowitz (2006)
Circ. Res. 99, 570-582
   Abstract »    Full Text »    PDF »
Role of Ubiquitylation in Cellular Membrane Transport.
O. Staub and D. Rotin (2006)
Physiol Rev 86, 669-707
   Abstract »    Full Text »    PDF »
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W. Wente, T. Stroh, A. Beaudet, D. Richter, and H.-J. Kreienkamp (2005)
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   Abstract »    Full Text »    PDF »
Dopamine responsiveness is regulated by targeted sorting of D2 receptors.
S. E. Bartlett, J. Enquist, F. W. Hopf, J. H. Lee, F. Gladher, V. Kharazia, M. Waldhoer, W. S. Mailliard, R. Armstrong, A. Bonci, et al. (2005)
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   Abstract »    Full Text »    PDF »
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C. Perrino, S. V. Naga Prasad, J. N. Schroder, J. A. Hata, C. Milano, and H. A. Rockman (2005)
Circulation 111, 2579-2587
   Abstract »    Full Text »    PDF »
c-Cbl Mediates Ubiquitination, Degradation, and Down-regulation of Human Protease-activated Receptor 2.
C. Jacob, G. S. Cottrell, D. Gehringer, F. Schmidlin, E. F. Grady, and N. W. Bunnett (2005)
J. Biol. Chem. 280, 16076-16087
   Abstract »    Full Text »    PDF »
The Composition of the {beta}-2 Adrenergic Receptor Oligomer Affects Its Membrane Trafficking after Ligand-Induced Endocytosis.
T. T. Cao, A. Brelot, and M. von Zastrow (2005)
Mol. Pharmacol. 67, 288-297
   Abstract »    Full Text »    PDF »
A. Heydorn, B. P. Sondergaard, B. Ersboll, B. Holst, F. C. Nielsen, C. R. Haft, J. Whistler, and T. W. Schwartz (2004)
J. Biol. Chem. 279, 54291-54303
   Abstract »    Full Text »    PDF »
Resistance of the Human {beta}1-Adrenergic Receptor to Agonist-induced Ubiquitination: A MECHANISM FOR IMPAIRED RECEPTOR DEGRADATION.
W. Liang and P. H. Fishman (2004)
J. Biol. Chem. 279, 46882-46889
   Abstract »    Full Text »    PDF »
Receptor activity-independent recruitment of {beta}arrestin2 reveals specific signalling modes.
S. Terrillon and M. Bouvier (2004)
EMBO J. 23, 3950-3961
   Abstract »    Full Text »    PDF »
Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization.
V. C. Dang and J. T. Williams (2004)
J. Neurosci. 24, 7699-7706
   Abstract »    Full Text »    PDF »
Caveolin-1 Interacts with 5-HT2A Serotonin Receptors and Profoundly Modulates the Signaling of Selected G{alpha}q-coupled Protein Receptors.
A. Bhatnagar, D. J. Sheffler, W. K. Kroeze, B. Compton-Toth, and B. L. Roth (2004)
J. Biol. Chem. 279, 34614-34623
   Abstract »    Full Text »    PDF »
Different Regulation of Human {delta}-Opioid Receptors by SNC-80 [(+)-4-[({alpha}R)-{alpha}-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and Endogenous Enkephalins.
I. Lecoq, N. Marie, Ph. Jauzac, and S. Allouche (2004)
J. Pharmacol. Exp. Ther. 310, 666-677
   Abstract »    Full Text »    PDF »
A Tyrosine-based Sorting Signal Regulates Intracellular Trafficking of Protease-activated Receptor-1: MULTIPLE REGULATORY MECHANISMS FOR AGONIST-INDUCED G PROTEIN-COUPLED RECEPTOR INTERNALIZATION.
M. M. Paing, B. R. S. Temple, and J. Trejo (2004)
J. Biol. Chem. 279, 21938-21947
   Abstract »    Full Text »    PDF »
Role of Mammalian Vacuolar Protein-sorting Proteins in Endocytic Trafficking of a Non-ubiquitinated G Protein-coupled Receptor to Lysosomes.
J. N. Hislop, A. Marley, and M. von Zastrow (2004)
J. Biol. Chem. 279, 22522-22531
   Abstract »    Full Text »    PDF »
Role of the Cyclic AMP-dependent Protein Kinase in Homologous Resensitization of the {beta}1-Adrenergic Receptor.
L. A. Gardner, N. M. D. Santos, S. G. Matta, M. A. Whitt, and S. W. Bahouth (2004)
J. Biol. Chem. 279, 21135-21143
   Abstract »    Full Text »    PDF »
Control of Aldosterone Secretion: A Model for Convergence in Cellular Signaling Pathways.
A. SPAT and L. HUNYADY (2004)
Physiol Rev 84, 489-539
   Abstract »    Full Text »    PDF »
GIPC Binds to the Human Lutropin Receptor (hLHR) through an Unusual PDZ Domain Binding Motif, and It Regulates the Sorting of the Internalized Human Choriogonadotropin and the Density of Cell Surface hLHR.
T. Hirakawa, C. Galet, M. Kishi, and M. Ascoli (2003)
J. Biol. Chem. 278, 49348-49357
   Abstract »    Full Text »    PDF »
Trafficking, Ubiquitination, and Down-regulation of the Human Platelet-activating Factor Receptor.
D. J. Dupre, Z. Chen, C. Le Gouill, C. Theriault, J.-L. Parent, M. Rola-Pleszczynski, and J. Stankova (2003)
J. Biol. Chem. 278, 48228-48235
   Abstract »    Full Text »    PDF »
A Novel Endocytic Recycling Signal That Distinguishes the Membrane Trafficking of Naturally Occurring Opioid Receptors.
M. Tanowitz and M. von Zastrow (2003)
J. Biol. Chem. 278, 45978-45986
   Abstract »    Full Text »    PDF »
Interaction Between the {micro} Opioid Receptor and Filamin A Is Involved in Receptor Regulation and Trafficking.
I. Onoprishvili, M. L. Andria, H. K. Kramer, N. Ancevska-Taneva, J. M. Hiller, and E. J. Simon (2003)
Mol. Pharmacol. 64, 1092-1100
   Abstract »    Full Text »    PDF »
Protease-Activated Receptors: New Concepts in Regulation of G Protein-Coupled Receptor Signaling and Trafficking.
J. Trejo (2003)
J. Pharmacol. Exp. Ther. 307, 437-442
   Abstract »    Full Text »    PDF »
Resistance of the Human {beta}1-Adrenergic Receptor to Agonist-mediated Down-regulation: ROLE OF THE C TERMINUS IN DETERMINING {beta}-SUBTYPE DEGRADATION.
W. Liang, S. Austin, Q. Hoang, and P. H. Fishman (2003)
J. Biol. Chem. 278, 39773-39781
   Abstract »    Full Text »    PDF »
Functional role of the NPxxY motif in internalization of the type 2 vasopressin receptor in LLC-PK1 cells.
R. Bouley, T.-X. Sun, M. Chenard, M. McLaughlin, M. McKee, H. Y. Lin, D. Brown, and D. A. Ausiello (2003)
Am J Physiol Cell Physiol 285, C750-C762
   Abstract »    Full Text »    PDF »
Y. Qiu, P.-Y. Law, and H. H. Loh (2003)
J. Biol. Chem. 278, 36733-36739
   Abstract »    Full Text »    PDF »
The Intracellular Trafficking of Opioid Receptors Directed by Carboxyl Tail and a Di-leucine Motif in Neuro2A Cells.
W. Wang, H. H. Loh, and P.-Y. Law (2003)
J. Biol. Chem. 278, 36848-36858
   Abstract »    Full Text »    PDF »
Selective Interactions between Helix VIII of the Human {micro}-Opioid Receptors and the C Terminus of Periplakin Disrupt G Protein Activation.
G.-J. Feng, E. Kellett, C. A. Scorer, J. Wilde, J. H. White, and G. Milligan (2003)
J. Biol. Chem. 278, 33400-33407
   Abstract »    Full Text »    PDF »
Regulation of {delta}-Opioid Receptor Trafficking via {micro}-Opioid Receptor Stimulation: Evidence from {micro}-Opioid Receptor Knock-Out Mice.
A. Morinville, C. M. Cahill, M. J. Esdaile, H. Aibak, B. Collier, B. L. Kieffer, and A. Beaudet (2003)
J. Neurosci. 23, 4888-4898
   Abstract »    Full Text »    PDF »
A Direct Interaction of PSD-95 with 5-HT2A Serotonin Receptors Regulates Receptor Trafficking and Signal Transduction.
Z. Xia, J. A. Gray, B. A. Compton-Toth, and B. L. Roth (2003)
J. Biol. Chem. 278, 21901-21908
   Abstract »    Full Text »    PDF »
Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Downregulation of bradykinin B2 receptor in human fibroblasts during prolonged agonist exposure.
A. Blaukat, P. Micke, I. Kalatskaya, A. Faussner, and W. Muller-Esterl (2003)
Am J Physiol Heart Circ Physiol 284, H1909-H1916
   Abstract »    Full Text »    PDF »
Binding of Filamin to the C-terminal Tail of the Calcitonin Receptor Controls Recycling.
T. Seck, R. Baron, and W. C. Horne (2003)
J. Biol. Chem. 278, 10408-10416
   Abstract »    Full Text »    PDF »
Ubiquitination-independent Trafficking of G Protein-coupled Receptors to Lysosomes.
M. Tanowitz and M. von Zastrow (2002)
J. Biol. Chem. 277, 50219-50222
   Abstract »    Full Text »    PDF »
J. A. Gray and B. L. Roth (2002)
Science 297, 529-531
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