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Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

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The Journal of Biological Chemistry





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Regulator of G protein signaling (RGS) proteins limit G protein signals. In this study, we investigated the role of RGS2 in the control of G protein signaling cascades in osteoblasts, the cells responsible for bone formation. Expression of RGS2 was up-regulated in primary cultures of mouse calvarial osteoblasts by parathyroid hormone-related peptide (PTHrP)-(1-34), which stimulates G(s) signaling. RGS2 was also up-regulated by extracellular ATP, which selectively activates G(q), as well as by forskolin and phorbol myristate acetate, which activate targets downstream of G(s) and G(q), respectively. To assess the role of endogenous RGS2, we characterized G(s) and G(q) signaling in osteoblasts derived from wild type and rgs2(-/-) mice. Under control conditions, nucleotide-stimulated calcium release, endothelin-stimulated accumulation of inositol phosphates, and PTHrP-stimulated cAMP accumulation were equivalent in osteoblasts isolated from wild type and rgs2(-/-) mice. Thus, basal levels of endogenous RGS2 do not appear to regulate G(s) or G(q) signaling in osteoblasts. Interestingly, forskolin treatment of wild type but not rgs2(-/-) osteoblasts suppressed both endothelin-stimulated accumulation of inositol phosphates and nucleotide-stimulated calcium release, indicating that up-regulation of RGS2 by G(s) signaling desensitizes G(q) signals. Furthermore, pretreatment with ATP suppressed PTHrP-dependent cAMP accumulation in wild type but not rgs2(-/-) osteoblasts, implying that up-regulation of RGS2 by G(q) signaling desensitizes G(s) signals. Our findings demonstrate that endogenously expressed RGS2 can limit G(s) signaling. Moreover, up-regulation of RGS2 contributes to cross-desensitization of G(s)- and G(q)-coupled signals.

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