Inducible RGS2 Is a Cross-Talk Regulator for Parathyroid Hormone Signaling in Rat Osteoblast-like UMR106 Cells

Abstract

Parathyroid hormone (PTH) activates dual signal transduction systems via Gαs and Gαq proteins. We now report a novel mechanism by which “cross-talk” may occur between the Gαs and Gαq 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 Gαs-mediated cAMP/PKA signaling pathway, whereas activation of the Gαq-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 Gαq pathway PMA did not. Pretreatment using the Gαs signaling pathway inhibitors SQ22536 and H89 significantly blocked PTH-induced RGS2 expression, but the Gαq signaling pathway inhibitor bisindolylmaleimide I had no effect. Therefore, RGS2 expression is governed solely by the Gαs signaling pathway. Additionally, we demonstrate for the first time that RGS2 binds to both Gαs and Gαq subunits in their transition state (GDP/AlF−4-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.