title: G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor.
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.
  
  
  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.
authors.affiliation: 7TM Pharma, Hoersholm, Denmark.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sanchez-Ferrer
authors.forename: Silvia
authors.initials: S
authors.lastname: Heringer-Walther
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Florian
authors.initials: F
authors.lastname: Gembardt
authors.forename: Elaine
authors.initials: E
authors.lastname: Kellett
authors.forename: Lene
authors.initials: L
authors.lastname: Martini
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanderheyden
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007295:Inositol Phosphates; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D002118:Calcium