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on April 4, 2005

A more recent version of this article appeared on April 12, 2005

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Submitted on July 25, 2004
Revised on November 22, 2004
Accepted on November 24, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: t.walther{at}erasmusmc.nl.

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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