β2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein
- Richard T. Premont*,†,
- Audrey Claing*,†,
- Nicolas Vitale‡,§,
- Jennifer L. R. Freeman*,
- Julie A. Pitcher,
- Walter A. Patton‡,
- Joel Moss‡,
- Martha Vaughan‡, and
- Robert J. Lefkowitz*,¶
- *Departments of Medicine (Cardiology) and Biochemistry, Howard Hughes Medical Institute, Box 3821, Duke University Medical Center, Durham, NC 27710; and ‡Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
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Contributed by Robert J. Lefkowitz
Abstract
G protein-coupled receptor activation leads to the membrane recruitment and activation of G protein-coupled receptor kinases, which phosphorylate receptors and lead to their inactivation. We have identified a novel G protein-coupled receptor kinase-interacting protein, GIT1, that is a GTPase-activating protein (GAP) for the ADP ribosylation factor (ARF) family of small GTP-binding proteins. Overexpression of GIT1 leads to reduced β2-adrenergic receptor signaling and increased receptor phosphorylation, which result from reduced receptor internalization and resensitization. These cellular effects of GIT1 require its intact ARF GAP activity and do not reflect regulation of GRK kinase activity. These results suggest an essential role for ARF proteins in regulating β2-adrenergic receptor endocytosis. Moreover, they provide a mechanism for integration of receptor activation and endocytosis through regulation of ARF protein activation by GRK-mediated recruitment of the GIT1 ARF GAP to the plasma membrane.
Footnotes
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↵ † R.T.P. and A.C. contributed equally to this work.
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↵ § Present address: Centre de Neurochimie, Institut National de la Santé et de la Recherche Médicale U-338, 5, rue Blaise Pascal, 67084 Strasbourg Cedex, France.
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↵ ¶ To whom reprint requests should be addressed. e-mail: lefko001{at}mc.duke.edu.
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Data deposition: The sequence reported in this paper has been deposited in the GenBank/EMBL databases [accession no. AF085693 (rat GIT1)].
- ABBREVIATIONS:
- ARF,
- ADP ribosylation factor;
- β2AR,
- β2-adrenergic receptor;
- GAP,
- GTPase-activating protein;
- GIT,
- GRK interactor;
- GRK,
- G protein-coupled receptor kinase
- Copyright © 1998, The National Academy of Sciences
