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J. Biol. Chem., Vol. 280, Issue 7, 5598-5604, February 18, 2005

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G Protein-coupled Receptor Endocytosis in ADP-ribosylation Factor 6-depleted Cells^*

Tanguy Houndolo, Pierre-Luc Boulay, and Audrey Claing

From the Department of Pharmacology, and the Membrane Protein Study Group, School of Medicine, University of Montréal, Montréal H3C 3J7, Canada

The internalization of G protein-coupled receptors is regulated by several important proteins that act in concert to finely control this complex cellular process. Here, we have applied the RNA interference approach to demonstrate that ADP-ribosylation factor 6 (ARF6) is essential for the endocytosis of a broad variety of receptors. Reduction of endogenous expression of ARF6 in HEK 293 cells resulted in a correlated inhibition of the ₂ -adrenergic receptor internalization previously characterized as being sequestered via the clathrin-coated vesicle pathway. Furthermore, other receptors internalizing via this endocytic route, namely the angiotensin type 1 receptor and the vasopressin type 2 receptor, were also impaired in their ability to be sequestered when levels of endogenous ARF6 in cells were reduced. Interestingly, endocytosis of the endothelin type B receptor, characterized as being internalized via the caveolae pathway, was also markedly inhibited in ARF6-depleted cells. In contrast, internalization of the vasoactive intestinal peptide receptor was unaffected by reduced levels of ARF6. Finally, internalization of the acetylcholine-muscarinic type 2 receptor via the non-clathrin-coated vesicle pathway was also inhibited in ARF6-depleted cells. Taken together, our results demonstrate that ARF6 proteins play an essential role in the internalization process of most G protein-coupled receptors regardless of the endocytic route being utilized. However, this phenomenon is not general. In some cases, another ARF isoform or other proteins may be essential to regulate the endocytic process.

Received for publication, October 7, 2004 , and in revised form, December 2, 2004.

^* This work was supported in part by the Canadian Institutes of Health Research Grant MOP-53199 and the Heart and Stroke Foundation of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A scholar of the Fonds de recherche sur la Nature et les Technologies. Tel.: 514-343-6352; Fax: 514-343-2291; E-mail: audrey.claing{at}umontreal.ca.

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