G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor.
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.
Kostenis
Evi
E
7TM Pharma, Hoersholm, Denmark.
Milligan
Graeme
G
Christopoulos
Arthur
A
Sanchez-Ferrer
Carlos F
CF
Heringer-Walther
Silvia
S
Sexton
Patrick M
PM
Gembardt
Florian
F
Kellett
Elaine
E
Martini
Lene
L
Vanderheyden
Patrick
P
Schultheiss
Heinz-Peter
HP
Walther
Thomas
T
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
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