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Molecular Pharmacology

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Research ArticleArticle

β-Arrestin- and Dynamin-Dependent Endocytosis of the AT1 Angiotensin Receptor

Zsuzsanna Gáborik, Márta Szaszák, László Szidonya, Borbála Balla, Sándor Paku, Kevin J. Catt, Adrian J. L. Clark and László Hunyady
Molecular Pharmacology February 2001, 59 (2) 239-247; DOI: https://doi.org/10.1124/mol.59.2.239
Zsuzsanna Gáborik
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Márta Szaszák
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László Szidonya
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Borbála Balla
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Sándor Paku
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Kevin J. Catt
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Adrian J. L. Clark
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László Hunyady
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Abstract

The major mechanism of agonist-induced internalization of G protein-coupled receptors (GPCRs) is β-arrestin- and dynamin-dependent endocytosis via clathrin-coated vesicles. However, recent reports have suggested that some GPCRs, exemplified by the AT1 angiotensin receptor expressed in human embryonic kidney (HEK) 293 cells, are internalized by a β-arrestin- and dynamin-independent mechanism, and possibly via a clathrin-independent pathway. In this study, agonist-induced endocytosis of the rat AT1A receptor expressed in Chinese hamster ovary (CHO) cells was abolished by clathrin depletion during treatment with hyperosmotic sucrose and was unaffected by inhibition of endocytosis via caveolae with filipin. In addition, internalized fluorescein-conjugated angiotensin II appeared in endosomes, as demonstrated by colocalization with transferrin. Overexpression of β-arrestin1(V53D) and β-arrestin1(1–349) exerted dominant negative inhibitory effects on the endocytosis of radioiodinated angiotensin II in CHO cells. GTPase-deficient (K44A) mutant forms of dynamin-1 and dynamin-2, and a pleckstrin homology domain-mutant (K535A) dynamin-2 with impaired phosphoinositide binding, also inhibited the endocytosis of AT1 receptors in CHO cells. Similar results were obtained in COS-7 and HEK 293 cells. Confocal microscopy using fluorescein-conjugated angiotensin II showed that overexpression of dynamin-1(K44A) and dynamin-2(K44A) isoforms likewise inhibited agonist-induced AT1 receptor endocytosis in CHO cells. Studies on the angiotensin II concentration-dependence of AT1 receptor endocytosis showed that at higher agonist concentrations its rate constant was reduced and the inhibitory effects of dominant negative dynamin constructs were abolished. These data demonstrate the importance of β-arrestin- and dynamin-dependent endocytosis of the AT1 receptor via clathrin-coated vesicles at physiological angiotensin II concentrations.

Footnotes

  • Send reprint requests to: Dr. László Hunyady, Department of Physiology, Semmelweis University Medical School, H-1444 Budapest, P. O. Box 259, Hungary. E-mail:hunyady{at}puskin.sote.hu

  • This work was supported in part by a Collaborative Research Initiative grant from the Wellcome Trust (051804/Z/97/Z), an International Research Scholar's award from the Howard Hughes Medical Institute (HHMI 75195–541702) and by grants from the Hungarian Ministry of Culture and Education (FKFP-0318/1999), the Hungarian Science Foundation (OTKA T-032179) and the Semmelweis University.

  • Preliminary data of this work were presented at the American Society for Cell Biology Annual Meeting, Washington, DC, December 1999 [Hunyady L, Gáborik Z, Mihalik B, Clark AJL, Catt KJ (1999) Dynamin-dependent mechanism of internalization of the AT1Aangiotensin receptor (Abstract). Mol Biol Cell 10:316a].

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (2)
Molecular Pharmacology
Vol. 59, Issue 2
1 Feb 2001
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Research ArticleArticle

β-Arrestin- and Dynamin-Dependent Endocytosis of the AT1 Angiotensin Receptor

Zsuzsanna Gáborik, Márta Szaszák, László Szidonya, Borbála Balla, Sándor Paku, Kevin J. Catt, Adrian J. L. Clark and László Hunyady
Molecular Pharmacology February 1, 2001, 59 (2) 239-247; DOI: https://doi.org/10.1124/mol.59.2.239

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Research ArticleArticle

β-Arrestin- and Dynamin-Dependent Endocytosis of the AT1 Angiotensin Receptor

Zsuzsanna Gáborik, Márta Szaszák, László Szidonya, Borbála Balla, Sándor Paku, Kevin J. Catt, Adrian J. L. Clark and László Hunyady
Molecular Pharmacology February 1, 2001, 59 (2) 239-247; DOI: https://doi.org/10.1124/mol.59.2.239
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