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.