Angiotensin metabolites can stimulate receptors of the Mas-related genes family

The Mas protooncogene encodes a G protein-coupled receptor, we identified, also by using the specific angiotensin-(1-7) antagonist A-779, to be associated with intracellular signaling of the angiotensin (Ang) II metabolite Ang-(1-7). Recently, Mas-related genes (Mrg) have been identified coding for the Mrg-receptor family. All family members share high sequence homology to Mas. Most of them are orphan receptors. To proof whether structure similarities of the Mrg receptors with Mas turn them into potential receptors for Ang-(1-7) or other Ang metabolites, we transfected COS or HEK293 cells with an assortment of Mrg receptors and investigated arachidonic acid (AA) release and transcriptional activation by recording serum response factor (SRF) activation after stimulation with Ang II, Ang III, Ang IV, and Ang-(1-7). None of the investigated receptors activated transcription via SRF. Ang-(1-7) stimulated AA release already in control vector-transfected COS cells, indicating the existence of an endogenous receptor (A-779 sensitive). Though less pronounced than for Mas, two of the six studied receptors (MrgD, MRG) initiated significant AA release after stimulation with Ang-(1-7). Interestingly, Mas, MrgD, and MRG mediated Ang IV-stimulated AA release that was highest for Mas. While Ang III activated Mas and MrgX2, Ang II stimulated AA release via Mas and MRG. Thus, we identified other receptors of the Mrg family to respond on Ang-(1-7) stimulation. Furthermore, we describe first an AT(1)-independent direct Ang IV signaling and show that Ang II and Ang III mediate signaling independent of their specific receptors AT(1) and AT(2), whereby the receptor specificity differs.