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A Polyaromatic Caveolin-Binding-Like Motif in the Cytoplasmic Tail of the Type 1 Receptor for Angiotensin II Plays an Important Role in Receptor Trafficking and Signaling

Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4

Address all correspondence and requests for reprints to: Gaétan Guillemette, Ph.D., Department of Pharmacology Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke (Québec), J1H 5N4, Canada. E-mail: Gaetan.Guillemette{at}USherbrooke.ca.

The type 1 receptor for angiotensin II (AT₁) is a member of the G protein-coupled receptor family. The presence of a caveolin-binding-like motif (XXXXXXX where is an aromatic residue) within the cytoplasmic tail of the AT₁ receptor suggests an implication for caveolae in the functionality of this receptor. We constructed a mutant AT₁ receptor where each of the aromatic residues in the caveolin-binding-like motif were replaced by alanine (AT₁-YFFY/A). Mutation of this motif considerably reduced the plasma membrane expression of the receptor that accumulated in a perinuclear compartment. The agonist-induced internalization rate of the AT₁-YFFY/A receptor was also significantly reduced. Finally, the AT₁-YFFY/A receptor was poorly activated as indicated by a low agonist-induced production of inositol phosphates. Unexpectedly, the proportion of AT₁ receptor found in caveolae was minor under basal conditions and did not increase under stimulated conditions. Coexpression of the AT₁ receptor with dopamine receptor interacting protein of 78 kDa, a protein implicated in the cellular routing of the dopamine D1 receptor, increased plasma membrane expression of the AT₁ receptor. However, dopamine receptor interacting protein of 78 kDa had no effect on the expression of the AT₁-YFFY/A receptor. Taken together, these results suggest that the caveolin-binding-like motif of the AT₁ receptor does not promote localization of the receptor to caveolae but rather may act as a docking site for regulatory proteins modulating the routing and the functionality of the receptor.

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