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J. Biol. Chem., Vol. 280, Issue 24, 23215-23224, June 17, 2005

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Involvement of Actin in Agonist-induced Endocytosis of the G Protein-coupled Receptor for Thromboxane A₂

OVERCOMING OF ACTIN DISRUPTION BY ARRESTIN-3 BUT NOT ARRESTIN-2^*

Geneviève Laroche, Moulay Driss Rochdi, Stéphane A. Laporte¶, and Jean-Luc Parent, Holds a New Investigator Award from the Canadian Institutes of Health Research||

From the Service de Rhumatologie, Département de Médecine, Faculté de Médecine and Centre de Recherche Clinique, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada and the ^¶Hormones and Cancer Research Unit, Department of Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada

The role of actin in endocytosis of G protein-coupled receptors is poorly defined. In the present study, we demonstrate that agents that depolymerize (latrunculin B and cytochalasin D) or stabilize (jasplakinolide) the actin cytoskeleton blocked agonist-induced endocytosis of the isoform of the thromboxane A₂ receptor (TP) in HEK293 cells. This suggests that endocytosis of TP requires active remodeling of the actin cytoskeleton. On the other hand, disruption of microtubules with colchicine did not affect endocytosis of the receptor. Expression of wild-type and mutant forms of the small GTPases RhoA and Cdc42 potently inhibited endocytosis of TP, further indicating a role for the dynamic regulation of the actin cytoskeleton in this pathway. Agonist treatment of TP in HEK293 cells resulted in the formation of actin stress fibers through G_q/11 signaling. Because we previously showed that endocytosis of TP is dependent on arrestins, we decided to explore the relation between arrestin-2 and -3 and actin in endocytosis of this receptor. Interestingly, we show that the inhibition of TP endocytosis by the actin toxins in HEK293 cells was overcome by the overexpression of arrestin-3, but not of arrestin-2. These results indicate that the actin cytoskeleton is not essential in arrestin-3-mediated endocytosis of TP. However, arrestin-3 could not promote endocytosis of the TPY339A and TPI343A carboxyl-terminal mutants when the actin cytoskeleton was disrupted. Our data provide new evidence that the actin cytoskeleton plays an essential role in TP endocytosis. Furthermore, our work suggests the existence of actin-dependent and -independent arrestin-mediated pathways of endocytosis.

Received for publication, December 14, 2004 , and in revised form, April 11, 2005.

^* This work was supported in part by a grant from the Canadian Institutes of Health Research (to J.-L. P.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

Recipient of a doctoral award from the Canadian Institutes of Health Research.

^|| To whom correspondence should be addressed: Service de Rhumatologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12th North Ave., Fleurimont, Quebec J1H 5N4, Canada. Tel.: 819-564-5264; Fax: 819-564-5265; E-mail: jean-luc.parent{at}USherbrooke.ca.

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