G-Protein–Coupled Receptor MrgD Is a Receptor for Angiotensin-(1–7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A

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Angiotensin (Ang)-(1–7) has cardiovascular protective effects and is the opponent of the often detrimental Ang II within the renin–angiotensin system. Although it is well accepted that the G-protein–coupled receptor Mas is a receptor for the heptapeptide, the lack in knowing initial signaling molecules stimulated by Ang-(1–7) prevented definitive characterization of ligand/receptor pharmacology as well as identification of further hypothesized receptors for the heptapeptide. The study aimed to identify a second messenger stimulated by Ang-(1–7) allowing confirmation as well as discovery of the heptapeptide’s receptors. Ang-(1–7) elevates cAMP concentration in primary cells, such as endothelial or mesangial cells. Using cAMP as readout in receptor-transfected human embryonic kidney (HEK293) cells, we provided pharmacological proof that Mas is a functional receptor for Ang-(1–7). Moreover, we identified the G-protein–coupled receptor MrgD as a second receptor for Ang-(1–7). Consequently, the heptapeptide failed to increase cAMP concentration in primary mesangial cells with genetic deficiency in both Mas and MrgD. Mice deficient in MrgD showed an impaired hemodynamic response after Ang-(1–7) administration. Furthermore, we excluded the Ang II type 2 receptor as a receptor for the heptapeptide but discovered that the Ang II type 2 blocker PD123319 can also block Mas and MrgD receptors. Our results lead to an expansion and partial revision of the renin–angiotensin system, by identifying a second receptor for Ang-(1–7), by excluding Ang II type 2 as a receptor for the heptapeptide, and by enforcing the revisit of such publications which concluded Ang II type 2 function by only using PD123319.

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