Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts
Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts
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DOI：
10.1074/jbc.m604416200
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发表时间：
2006-10-27
影响因子：
4.8
通讯作者：
Chidiac, Peter
中科院分区：
文献类型：
--
作者：
Roy, Anju Anne;Nunn, Caroline;Chidiac, Peter
G蛋白信号传导调节因子（Regulator of G protein signaling，RGS）蛋白限制G蛋白信号。在这项研究中，我们研究了RGS 2在控制成骨细胞（负责骨形成的细胞）中G蛋白信号级联中的作用。在小鼠颅骨成骨细胞的原代培养物中，RGS 2的表达被甲状旁腺素相关肽（PTHrP）-（1-34）上调，其刺激Gs信号传导。RGS 2也被细胞外ATP上调，其选择性激活G（q），以及被毛喉素和佛波醇肉豆蔻酸酯乙酸酯上调，其分别激活G（s）和G（q）下游的靶点。为了评估内源性RGS 2的作用，我们表征了来自野生型和RGS 2（-/-）小鼠的成骨细胞中的Gs和Gq信号传导。在对照条件下，核苷酸刺激的钙释放，内皮素刺激的肌醇磷酸盐的积累，和PTHrP刺激的cAMP积累是等同的成骨细胞分离自野生型和rgs 2（-/-）小鼠。因此，内源性RGS 2的基础水平似乎不调节成骨细胞中的G（s）或G（q）信号传导。有趣的是，毛喉素处理野生型成骨细胞而不是rgs 2（-/-）成骨细胞抑制了内皮素刺激的磷酸肌醇积累和核苷酸刺激的钙释放，表明G（s）信号上调RGS 2使G（q）信号脱敏。此外，ATP预处理抑制PTHrP依赖性cAMP在野生型成骨细胞中的积累，但不抑制RGS 2（-/-）成骨细胞，这意味着G（q）信号上调RGS 2使G（s）信号脱敏。我们的研究结果表明，内源性表达的RGS 2可以限制G（s）信号传导。此外，RGS 2的上调有助于G（s）和G（q）耦合信号的交叉脱敏。
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 Gs 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 Gs and Gq 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.