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Mutational Analysis of the Conserved Asp^2.50 and ERY Motif Reveals Signaling Bias of the Urotensin II Receptor

Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada

Class A (rhodopsin-like) G protein-coupled receptors possess conserved residues and motifs that are important for their specific activity. In the present study, we examined the role of residue Asp97^2.50 as well as residues Glu147^3.49, Arg148^3.50, and Tyr149^3.51 of the ERY motif on the functionality of the urotensin II receptor (UT). Mutations D97^2.50A, R148^3.50A, and R148^3.50H abolished the ability of UT to activate phospholipase C, whereas mutations E147^3.49A and Y149^3.51A reduced the ability to activate PLC by 50%. None of the mutants exhibited constitutive activity. However, R148^3.50A and R148^3.50H promoted ERK1/2 activation, which was abolished by 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478), an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both these mutants were capable of directly activating EGFR, which confirmed that they activated the mitogen-activated protein kinase (MAPK) pathway by a G_q/11-independent transactivation of EGFR. The D97^2.50A, R148^3.50A, and R148^3.50H mutants did not readily internalize and did not promote translocation or colocalize with β-arrestin2-GFP. Finally, the agonist-induced internalization of the E147^3.49A mutant receptor was significantly increased compared with wild-type receptor. This study highlights the major contribution of the conserved Asp^2.50 residue to the functionality of the UT receptor. The Arg residue in the ERY motif of UT is an important structural element in signaling crossroads that determine whether G_q/11-dependent and -independent events can occur.

Address correspondence to: Richard Leduc, Ph.D. Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, ON, Canada. E-mail: richard.leduc{at}usherbrooke.ca

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