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(Circulation. 2005;111:1806-1813.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

G-Protein–Coupled Receptor Mas Is a Physiological Antagonist of the Angiotensin II Type 1 Receptor

Evi Kostenis, PhD; Graeme Milligan, PhD; Arthur Christopoulos, PhD; Carlos F. Sanchez-Ferrer, MD, PhD; Silvia Heringer-Walther, MD, PhD; Patrick M. Sexton, PhD; Florian Gembardt, MPharm; Elaine Kellett, DPhil; Lene Martini, PhD; Patrick Vanderheyden, PhD; Heinz-Peter Schultheiss, MD; Thomas Walther, PhD

From 7TM Pharma (E. Kostenis, L.M.), Hoersholm, Denmark; Molecular Pharmacology Group (G.M., E. Kellett), Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland; Department of Pharmacology (A.C.) and Howard Florey Institute of Experimental Physiology and Medicine (P.M.S.), The University of Melbourne, Parkville, Victoria, Australia; Department of Pharmacology, Facultad de Medicina, Universidad Autonoma (C.F.S.-F.), Madrid, Spain; Department of Pharmacology, Erasmus Medical Center (S.H.-W., F.G., T.W.), Rotterdam, the Netherlands; Department of Cardiology, Charité Berlin (F.G., H.-P.S., T.W.), Campus Benjamin Franklin, Berlin, Germany; and Department of Molecular and Biochemical Pharmacology (P.V.), Vrije Universiteit Brussel, Brussels, Belgium.

Correspondence to Thomas Walther, PhD, Department of Pharmacology, Erasmus Medical Center, Dr. Molewaterplein 50, 3000 DR Rotterdam, The Netherlands. E-mail t.walther{at}erasmusmc.nl

Received July 25, 2004; revision received November 22, 2004; accepted November 24, 2004.

Background— We previously identified the G-protein–coupled receptor Mas, encoded by the Mas proto-oncogene, as an endogenous receptor for the heptapeptide angiotensin-(1-7); however, the receptor is also suggested to be involved in actions of angiotensin II. We therefore tested whether this could be mediated indirectly through an interaction with the angiotensin II type 1 receptor, AT₁.

Methods and Results— In transfected mammalian cells, Mas was not activated by angiotensin II; however, AT₁ receptor–mediated, angiotensin II–induced production of inositol phosphates and mobilization of intracellular Ca²⁺ was diminished by 50% after coexpression of Mas, despite a concomitant increase in angiotensin II binding capacity. Mas and the AT₁ receptor formed a constitutive hetero-oligomeric complex that was unaffected by the presence of agonists or antagonists of the 2 receptors. In vivo, Mas acts as an antagonist of the AT₁ receptor; mice lacking the Mas gene show enhanced angiotensin II–mediated vasoconstriction in mesenteric microvessels.

Conclusions— These results demonstrate that Mas can hetero-oligomerize with the AT₁ receptor and by so doing inhibit the actions of angiotensin II. This is a novel demonstration that a G-protein–coupled receptor acts as a physiological antagonist of a previously characterized receptor. Consequently, the AT₁-Mas complex could be of great importance as a target for pharmacological intervention in cardiovascular diseases.

Key Words: angiotensin • calcium • muscle, smooth • vasoconstriction • receptors

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