The mas oncogene receptor has been reported to confer angiotensin (Ang) responsiveness in NG115-401L neuronal cell line. To test if mas oncogene encodes an Ang receptor in peripheral tissue, Balb 3T3 and rat aortic vascular smooth muscle cells (VSMC) were cotransfected with a plasmid containing the mas oncogene (pSM422) and a plasmid expressing a selectable marker (pRSV-Neo). Transfected cells (Balb/mas and VSMC/mas) expressed the appropriate 2.4 Kb mas transcript, which was not present in parental cells. Both Balb/mas and VSMC/mas cells acquired Ang II and Ang III responsiveness as documented by Ang-stimulated increased [Ca2+]i. The ED50for these peptides were relatively high (4−6 × 10−5M). Ang III was approximately two times more potent than Ang II in stimulating45Ca efflux from Balb/mas cells, and its effect was not blocked by SarI, Ile8-Ang II. In contrast, substance P and a substance P analogue ([D-Arg1, D-Pro2, D-Trp7,9, Leu11] substance P) behaved as agonists, resulting in the stimulation of45Ca efflux and [Ca2+]iin Balb/mas cells without affecting control cells. The rank order potency for stimulating45Ca efflux in Balb/mas cells was substance P analogue»Ang III, substance P>Ang II. In summary, the authors show that although Ang III can stimulate biochemical events in mas transfected cells, which are known to be essential for Ang receptor signal transduction in other cell types, ie, [Ca2+]iand pHitransients, as well as inositol triphosphate formation, it did that at supraphysiological concentrations of the peptide.