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Falk Cardiovascular Research Center and Department of Medicine
(L.H., R.E.P., V.J.D., B.K.K.) Howard Hughes Medical Institute
(B.K.K.) Stanford University School of Medicine Stanford,
California 94305
Department of Pharmacology (L.H., L.M.)
University of Wuerzburg Wuerzburg, Germany
Department of
Medicine (R.E.P, V.J.D.) Brigham and Womens Hospital Harvard
Medical School Boston, Massachusetts 02115
Angiotensin II (Ang II) binds to two different receptor subtypes, AT1 and AT2 receptors. In many cases, receptor stimulation by Ang II is followed by a rapid desensitization of the intracellular signal transduction and a decrease in cell surface receptor number. The present study was designed to examine by immunofluorescence microscopy the cellular trafficking pathways of Ang II and its AT1a and AT2 receptors in human embryonal kidney 293 cells stably expressing these receptor subtypes. Fluorescently labeled Ang II and AT1a receptors were rapidly internalized into endosomes. AT2 receptors were localized in the plasma membrane and did not undergo endocytosis upon agonist stimulation. After removal of agonist, AT1a receptors recycled to the plasma membrane, whereas fluorescently labeled Ang II was targeted to the lysosomal pathway. Even though no further loss of surface receptor was measurable by ligand binding at steady state, fluorescein-Ang II was continuously internalized, and cycling of receptor between endosomal vesicles and the plasma membrane was detected by antibody feeding. These experiments provide evidence for subtype-specific receptor sorting and internalization of Ang II and its AT1a receptor as a receptor-ligand complex, and they suggest that the sequestration of receptors into endosomes is in dynamic equilibrium with receptor cycling to the plasma membrane. Finally, internalization of AT1a receptors and Ang II persists after desensitization mechanisms have attenuated Ca2+ and inositol 1,4,5-trisphosphate signaling.
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S. S. G. Ferguson Evolving Concepts in G Protein-Coupled Receptor Endocytosis: The Role in Receptor Desensitization and Signaling Pharmacol. Rev., March 1, 2001; 53(1): 1 - 24. [Abstract] [Full Text] [PDF] |
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L G. Navar, K. D Mitchell, L. M Harrison-Bernard, H. Kobori, and A. Nishiyama Review: Intrarenal angiotensin II levels in normal and hypertensive states Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S176 - S184. [PDF] |
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L. Gendron*, L. Laflamme*, N. Rivard, C. Asselin, M. D. Payet, and N. Gallo-Payet Signals from the AT2 (Angiotensin Type 2) Receptor of Angiotensin II Inhibit p21ras and Activate MAPK (Mitogen-Activated Protein Kinase) to Induce Morphological Neuronal Differentiation in NG108-15 Cells Mol. Endocrinol., September 1, 1999; 13(9): 1615 - 1626. [Abstract] [Full Text] |
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K. Nakamura, M. d. F. M. Lazari, S. Li, C. Korgaonkar, and M. Ascoli Role of the Rate of Internalization of the Agonist-Receptor Complex on the Agonist-Induced Down-Regulation of the Lutropin/ Choriogonadotropin Receptor Mol. Endocrinol., August 1, 1999; 13(8): 1295 - 1304. [Abstract] [Full Text] |
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J. D. Imig, G. L. Navar, L.-X. Zou, K. C. O'Reilly, P. L. Allen, J. H. Kaysen, T. G. Hammond, and L. G. Navar Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors Am J Physiol Renal Physiol, August 1, 1999; 277(2): F303 - F311. [Abstract] [Full Text] [PDF] |
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L. Daviet, J. Y. A. Lehtonen, K. Tamura, D. P. Griese, M. Horiuchi, and V. J. Dzau Cloning and Characterization of ATRAP, a Novel Protein That Interacts with the Angiotensin II Type 1 Receptor J. Biol. Chem., June 11, 1999; 274(24): 17058 - 17062. [Abstract] [Full Text] [PDF] |
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