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J. Biol. Chem., Vol. 281, Issue 43, 32684-32693, October 27, 2006

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Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between G_s and G_q Signaling in Osteoblasts^*

Anju Anne Roy¹², Caroline Nunn¹³, Hong Ming¹, Min-Xu Zou³, Josef Penninger, Lorrie A. Kirshenbaum^¶4, S. Jeffrey Dixon^||, and Peter Chidiac⁵

From the Department of Physiology and Pharmacology, ^||Canadian Institutes of Health Research Group in Skeletal Development and Remodeling, the University of Western Ontario, London, Ontario N6A 5C1, Canada, the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria, and the ^¶Department of Physiology, Institute of Cardiovascular Sciences, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada

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.

Received for publication, May 9, 2006 , and in revised form, August 2, 2006.

^* This work was supported in part by grants from the Canadian Institutes of Health Research (to P. C. and S. J. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Supported by studentships from the Natural Sciences and Engineering Research Council of Canada and the Heart and Stroke Foundation of Canada.

³ Supported by the Heart and Stroke Foundation of Ontario Program Grant in Heart Failure.

⁴ Holds a Canada Research Chair in Molecular Cardiology.

⁵ To whom correspondence should be addressed. Tel.: 519-661-3318; Fax: 519-661-3827; E-mail: Peter.Chidiac{at}schulich.uwo.ca.

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