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首页> 外文期刊>Cellular Signalling >Antagonist minigenes identify genes regulated by parathyroid hormone through G protein-selective and G protein co-regulated mechanisms in osteoblastic cells
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Antagonist minigenes identify genes regulated by parathyroid hormone through G protein-selective and G protein co-regulated mechanisms in osteoblastic cells

机译：拮抗小基因通过成骨细胞中的G蛋白选择性和G蛋白共同调控机制识别甲状旁腺激素调控的基因

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Parathyroid hormone (PTH) is the major hormone regulating bone remodeling. Binding of PTH to the PTH1 receptor (PTH1R), a heterotrimeric G protein coupled receptor (GPCR), can potentially trigger multiple signal transduction pathways mediated through several different G proteins. In this study, we employed G protein antagonist minigenes inhibiting Gα_s, Gα_q or Gα_(12) to selectively dissect out which of these G proteins were responsible for effects of PTH(1-34) in targeted signaling and osteogenesis arrays consisting of 159 genes. Among the 32 genes significantly regulated by 24h PTH treatment in UMR-106 osteoblastic cells, 9 genes were exclusively regulated through G_s, 6 genes were solely mediated through G_q, and 3 genes were only controlled through G_(12). Such findings support the concept that there is some absolute specificity in downstream responses initiated at the G protein level following binding of PTH to the PTH1R. On the other hand, 6 PTH-regulated genes were regulated by both G_s and G_q, 3 genes were regulated by both G_s and G_(12), and 3 genes were controlled by G_s, G_q and G_(12). These findings indicate potential overlapping or sequential interactions among different G protein-mediated pathways. In addition, two PTH-regulated genes were not regulated through any of the G proteins examined, suggesting that additional signaling mechanisms may be involved. Selectivity was largely maintained over a 2-48-hour time period. The minigene effects were mimicked by downstream inhibitors. The dissection of the differential effects of multiple G protein pathways on gene regulation provides a more complete understanding of PTH signaling in osteoblastic cells.
机译：甲状旁腺激素（PTH）是调节骨骼重塑的主要激素。 PTH与PTH1受体（PTH1R）（异三聚体G蛋白偶联受体（GPCR））的结合可能会触发通过几种不同G蛋白介导的多种信号转导途径。在这项研究中，我们采用了抑制Gα_s，Gα_q或Gα_（12）的G蛋白拮抗剂小基因，选择性地剖析了这些G蛋白中哪些负责PTH（1-34）在由159个基因组成的靶向信号传导和成骨阵列中的作用。在UMR-106成骨细胞中，经过24h PTH处理后显着调控的32个基因中，有9个基因仅通过G_s调控，有6个基因仅通过G_q介导，而3个基因仅通过G_（12）控制。这些发现支持了这样的概念，即在PTH与PTH1R结合后，在G蛋白水平上引发的下游反应中存在一定的绝对特异性。另一方面，G_s和G_q均调节了6个PTH调节基因，G_s和G_（12）均调节了3个基因，G_s，G_q和G_（12）调节了3个基因。这些发现表明不同的G蛋白介导的途径之间潜在的重叠或顺序相互作用。此外，两个PTH调控的基因不受任何G蛋白的调控，表明可能涉及其他信号传导机制。选择性在2-48小时的时间内得到了很大程度的保持。小基因的作用被下游抑制剂模仿。多种G蛋白途径对基因调控的差异作用的剖析为成骨细胞中PTH信号传导提供了更完整的理解。

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