Parathyroid hormone (PTH) activates dual signal transduction systems via G alphas and G alphaq proteins. We now report a novel mechanism by which "cross-talk" may occur between the G alphas and G alphaq signaling pathways. RGS2 (Regulator of G protein Signaling 2) mRNA was rapidly and transiently increased only by PTH analogs (PTH1-84, 1-34, 1-31, and PTHrP) that activated the G alphas-mediated cAMP/PKA signaling pathway, whereas activation of the G alphaq-mediated Ca2+/PKC signaling pathway by PTH3-34 had no effect on RGS2 expression. Treatment of UMR106 cells with nonPTH activators of the cAMP/PKA signaling pathway such as cholera toxin, forskolin, 8-Br-cAMP, and dibutyryl-cAMP also significantly elevated RGS2 mRNA levels, while activator of the G alphaq pathway PMA did not. Pretreatment using the G alphas signaling pathway inhibitors SQ22536 and H89 significantly blocked PTH-induced RGS2 expression, but the G alphaq signaling pathway inhibitor bisindolylmaleimide I had no effect. Therefore, RGS2 expression is governed solely by the G alphas signaling pathway. Additionally, we demonstrate for the first time that RGS2 binds to both G alphas and G alphaq subunits in their transition state (GDP/AlF4--bound) forms, suggesting that RGS2 has the potential to act as a bridge between the cAMP/PKA and Ca2+/PKC pathways, and that it may act as a cross-talk regulator for these two PTH signaling pathways.