© The Rockefeller University Press,
0021-9525/1999//31 $5.00
The Journal of Cell Biology, Volume 144, Number 1,
, 1999 31-43
Distinct Dynamin-dependent and -independent Mechanisms Target Structurally Homologous Dopamine Receptors to Different Endocytic Membranes
Ross G. Vickery and
Mark von Zastrow
Department of Psychiatry and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143-0984
D1 and D2 dopamine receptors are structurally homologous G protein–coupled receptors that serve distinct physiological functions both in neurons and nonneural cell types. We have observed that these receptors are selectively endocytosed in HEK293 cells by distinct dynamin-dependent and -independent mechanisms. Although these endocytic mechanisms operate with similarly rapid kinetics, they differ in their regulation by agonist and deliver D1 and D2 receptors specifically to different primary endocytic vesicles. After this segregation into different endocytic membranes, both D1 and D2 receptors recycle to the plasma membrane. Similar results are observed in Neuro2A neuroblastoma cells coexpressing both receptors at high levels. These findings establish that "classical" dynamin-dependent and "alternative" dynamin-independent endocytic mechanisms differ in their physiological regulation, sort structurally homologous signaling receptors in the plasma membrane, and mediate distinct early endocytic pathways leading to recycling endosomes. Our results also refute the previous hypothesis that dynamin-independent endocytosis targets G protein–coupled receptors selectively to lysosomes, and they suggest a new role of endocytic sorting mechanisms in physically segregating structurally homologous signaling receptors at the cell surface.
Key Words: receptor endocytosis dopamine cell membrane cell physiology
Abbreviations used in this paper: HEK, human embryonic kidney.
These studies were funded by a grant from the National Alliance for Research on Schizophrenia and Depression (to R.G. Vickery), a postdoctoral training fellowship from the National Institutes of Health (to R.G. Vickery), and a research grant from the Tourette Syndrome Association (to M. von Zastrow). R.G. Vickery is a Staglin Fellow in Molecular Neurobiology.

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-
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-
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-
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-
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-
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-
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-
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-
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-
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[Full Text]
-
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(2003). Protease-Activated Receptors: New Concepts in Regulation of G Protein-Coupled Receptor Signaling and Trafficking. J. Pharmacol. Exp. Ther.
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[Full Text]
-
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(2003). shibire mutations reveal distinct dynamin-independent and -dependent endocytic pathways in primary cultures of Drosophila hemocytes. J. Cell Sci.
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[Abstract]
[Full Text]
-
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(2003). Agonist-independent Desensitization and Internalization of the Human Platelet-activating Factor Receptor by Coumermycin-Gyrase B-induced Dimerization. J. Biol. Chem.
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[Full Text]
-
Fourgeaud, L., Bessis, A.-S., Rossignol, F., Pin, J.-P., Olivo-Marin, J.-C., Hemar, A.
(2003). The Metabotropic Glutamate Receptor mGluR5 Is Endocytosed by a Clathrin-independent Pathway. J. Biol. Chem.
278: 12222-12230
[Abstract]
[Full Text]
-
Kabbani, N., Negyessy, L., Lin, R., Goldman-Rakic, P., Levenson, R.
(2002). Interaction with Neuronal Calcium Sensor NCS-1 Mediates Desensitization of the D2 Dopamine Receptor. J. Neurosci.
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[Abstract]
[Full Text]
-
Magalhaes, A. C., Silva, J. A., Lee, K. S., Martins, V. R., Prado, V. F., Ferguson, S. S. G., Gomez, M. V., Brentani, R. R., Prado, M. A. M.
(2002). Endocytic Intermediates Involved with the Intracellular Trafficking of a Fluorescent Cellular Prion Protein. J. Biol. Chem.
277: 33311-33318
[Abstract]
[Full Text]
-
Mason, J. N., Kozell, L. B., Neve, K. A.
(2002). Regulation of Dopamine D1 Receptor Trafficking by Protein Kinase A-Dependent Phosphorylation. Mol. Pharmacol.
61: 806-816
[Abstract]
[Full Text]
-
Wong, D. F.
(2002). In Vivo Imaging of D2 Dopamine Receptors in Schizophrenia: The Ups and Downs of Neuroimaging Research. Arch Gen Psychiatry
59: 31-34
[Full Text]
-
Oak, J. N., Lavine, N., Van Tol, H. H. M.
(2001). Dopamine D4 and D2L Receptor Stimulation of the Mitogen-Activated Protein Kinase Pathway Is Dependent on trans-Activation of the Platelet-Derived Growth Factor Receptor. Mol. Pharmacol.
60: 92-103
[Abstract]
[Full Text]
-
Roseberry, A. G., Bünemann, M., Elavunkal, J., Hosey, M. M.
(2001). Agonist-Dependent Delivery of M2 Muscarinic Acetylcholine Receptors to the Cell Surface after Pertussis Toxin Treatment. Mol. Pharmacol.
59: 1256-1268
[Abstract]
[Full Text]
-
Gáborik, Z., Szaszák, M., Szidonya, L., Balla, B., Paku, S., Catt, K. J., Clark, A. J. L., Hunyady, L.
(2001). {beta}-Arrestin- and Dynamin-Dependent Endocytosis of the AT1 Angiotensin Receptor. Mol. Pharmacol.
59: 239-247
[Abstract]
[Full Text]
-
Gardner, B., Liu, Z. F., Jiang, D., Sibley, D. R.
(2001). The Role of Phosphorylation/Dephosphorylation in Agonist-Induced Desensitization of D1 Dopamine Receptor Function: Evidence for a Novel Pathway for Receptor Dephosphorylation. Mol. Pharmacol.
59: 310-321
[Abstract]
[Full Text]
-
Prou, D., Gu, W.-J., Le Crom, S., Vincent, J.-D., Salamero, J., Vernier, P.
(2001). Intracellular retention of the two isoforms of the D2 dopamine receptor promotes endoplasmic reticulum disruption. J. Cell Sci.
114: 3517-3527
[Abstract]
[Full Text]
-
Barbieri, M. A., Roberts, R. L., Gumusboga, A., Highfield, H., Alvarez-Dominguez, C., Wells, A., Stahl, P. D.
(2000). Epidermal Growth Factor and Membrane Trafficking: Egf Receptor Activation of Endocytosis Requires Rab5a. JCB
151: 539-550
[Abstract]
[Full Text]
-
Wilson, J. M., de Hoop, M., Zorzi, N., Toh, B.-H., Dotti, C. G., Parton, R. G.
(2000). EEA1, a Tethering Protein of the Early Sorting Endosome, Shows a Polarized Distribution in Hippocampal Neurons, Epithelial Cells, and Fibroblasts. Mol. Biol. Cell
11: 2657-2671
[Abstract]
[Full Text]
-
Tsao, P. I., von Zastrow, M.
(2000). Type-specific Sorting of G Protein-coupled Receptors after Endocytosis. J. Biol. Chem.
275: 11130-11140
[Abstract]
[Full Text]
-
Li, M., Bermak, J. C., Wang, Z. W., Zhou, Q. Y.
(2000). Modulation of Dopamine D2 Receptor Signaling by Actin-Binding Protein (ABP-280). Mol. Pharmacol.
57: 446-452
[Abstract]
[Full Text]
-
Nicoziani, P., Vilhardt, F., Llorente, A., Hilout, L., Courtoy, P. J., Sandvig, K., van Deurs, B.
(2000). Role for Dynamin in Late Endosome Dynamics and Trafficking of the Cation-independent Mannose 6-Phosphate Receptor. Mol. Biol. Cell
11: 481-495
[Abstract]
[Full Text]
-
Olli-Lahdesmaki, T., Kallio, J., Scheinin, M.
(1999). Receptor Subtype-Induced Targeting and Subtype-Specific Internalization of Human alpha 2-Adrenoceptors in PC12 Cells. J. Neurosci.
19: 9281-9288
[Abstract]
[Full Text]
-
Melikian, H. E., Buckley, K. M.
(1999). Membrane Trafficking Regulates the Activity of the Human Dopamine Transporter. J. Neurosci.
19: 7699-7710
[Abstract]
[Full Text]
-
Schramm, N. L., Limbird, L. E.
(1999). Stimulation of Mitogen-activated Protein Kinase by G Protein-coupled alpha 2-Adrenergic Receptors Does Not Require Agonist-elicited Endocytosis. J. Biol. Chem.
274: 24935-24940
[Abstract]
[Full Text]
-
Bunemann, M., Hosey, M M.
(1999). G-protein coupled receptor kinases as modulators of G-protein signalling. J. Physiol.
517: 5-23
[Abstract]
[Full Text]
-
Skretting, G, Torgersen, M., van Deurs, B, Sandvig, K
(1999). Endocytic mechanisms responsible for uptake of GPI-linked diphtheria toxin receptor. J. Cell Sci.
112: 3899-3909
[Abstract]
-
Werbonat, Y., Kleutges, N., Jakobs, K. H., van Koppen, C. J.
(2000). Essential Role of Dynamin in Internalization of M2 Muscarinic Acetylcholine and Angiotensin AT1A Receptors. J. Biol. Chem.
275: 21969-21974
[Abstract]
[Full Text]
-
Schlador, M. L., Grubbs, R. D., Nathanson, N. M.
(2000). Multiple Topological Domains Mediate Subtype-specific Internalization of the M2 Muscarinic Acetylcholine Receptor. J. Biol. Chem.
275: 23295-23302
[Abstract]
[Full Text]
-
Trejo, J., Altschuler, Y., Fu, H.-W., Mostov, K. E., Coughlin, S. R.
(2000). Protease-activated Receptor-1 Down-regulation. A MUTANT HeLa CELL LINE SUGGESTS NOVEL REQUIREMENTS FOR PAR1 PHOSPHORYLATION AND RECRUITMENT TO CLATHRIN-COATED PITS. J. Biol. Chem.
275: 31255-31265
[Abstract]
[Full Text]
-
Schmidlin, F., Dery, O., DeFea, K. O., Slice, L., Patierno, S., Sternini, C., Grady, E. F., Bunnett, N. W.
(2001). Dynamin and Rab5a-dependent Trafficking and Signaling of the Neurokinin 1 Receptor. J. Biol. Chem.
276: 25427-25437
[Abstract]
[Full Text]
-
Whistler, J. L., Tsao, P., von Zastrow, M.
(2001). A Phosphorylation-regulated Brake Mechanism Controls the Initial Endocytosis of Opioid Receptors but Is Not Required for Post-endocytic Sorting to Lysosomes. J. Biol. Chem.
276: 34331-34338
[Abstract]
[Full Text]
-
Cong, M., Perry, S. J., Hu, L. A., Hanson, P. I., Claing, A., Lefkowitz, R. J.
(2001). Binding of the beta 2 Adrenergic Receptor to N-Ethylmaleimide-sensitive Factor Regulates Receptor Recycling. J. Biol. Chem.
276: 45145-45152
[Abstract]
[Full Text]
-
Kim, K.-M., Valenzano, K. J., Robinson, S. R., Yao, W. D., Barak, L. S., Caron, M. G.
(2001). Differential Regulation of the Dopamine D2 and D3 Receptors by G Protein-coupled Receptor Kinases and beta -Arrestins. J. Biol. Chem.
276: 37409-37414
[Abstract]
[Full Text]
-
Saunders, C., Ferrer, J. V., Shi, L., Chen, J., Merrill, G., Lamb, M. E., Leeb-Lundberg, L. M. F., Carvelli, L., Javitch, J. A., Galli, A.
(2000). Amphetamine-induced loss of human dopamine transporter activity: An internalization-dependent and cocaine-sensitive mechanism. Proc. Natl. Acad. Sci. USA
97: 6850-6855
[Abstract]
[Full Text]