G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor

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

Research output: Contribution to journalArticlepeer-review

357 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1806-1813
Number of pages8
JournalCirculation
Volume111
Issue number14
DOIs
Publication statusPublished - 12 Apr 2005

Keywords

  • Angiotensin II
  • Angiotensin II Type 1 Receptor Blockers
  • Animals
  • CHO Cells
  • Calcium
  • Cricetinae
  • In Vitro Techniques
  • Inositol Phosphates
  • Mesenteric Arteries
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Transfection
  • Vasoconstriction
  • Research Support, Non-U.S. Gov't

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