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首页> 外文期刊>Cellular Signalling >Gα_h/transglutaminase-2 activity is required for maximal activation of adenylylcyclase 8 in human and rat glioma cells
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Gα_h/transglutaminase-2 activity is required for maximal activation of adenylylcyclase 8 in human and rat glioma cells

机译：Gα_h/ transglutaminase-2活性是人类和大鼠神经胶质瘤细胞中最大程度激活腺苷酸环化酶8所必需的

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摘要

Gα_h (or transglutaminase-2 (TG2)) is an atypical guanine nucleotide binding-protein that associates with G protein-coupled receptors. TG2 also exerts transglutaminase activity that catalyzes posttranslational protein cross-linking with the formation of ε-(γ-glutamyl) lysine or (γ-glutamyl) polyamine bonds. Here, the role of Gα_h/TG2 in signal transduction in glial cells was examined in detail. In 1321N1 human astrocytoma cells that lack Gα_h/TG2, overexpression of Gα_h/TG2 caused an enhancement of cAMP accumulation stimulated with the β-adrenergic receptor agonist, isoproterenol, or the adenylylcyclase activator, forskolin. This cAMP-enhancement was reversed by the TG2 inhibitor, ERW1069. In rat C6 glioma cells that express endogenous Gα_h/TG2, cAMP accumulation induced by isoproterenol or forskolin was significantly inhibited by overexpression of Gα_h/TG2-C277V, a dominant-negative mutant that lacks transglutaminase activity, but was not inhibited by the Gα_h/TG2-S171E mutant that cannot bind GTP/GDP. These results suggest Gα_h/TG2 potentiates adenylylcyclase activity by its transglutaminase activity and not by its G-protein activity. Gα_h/TG2 also increased the activities of the cAMP response element and interleukin-6 promoter, accompanied by an of cAMP in both glioma cells. Since adenylylcyclase 8 plays a major role in cAMP production, we focused on post-translational modification of adenylylcyclase 8 by Gα_h/TG2. Adenylylcyclase 8 is expressed in both 1321N1 and C6 cells; however, Gα_h/TG2 affected neither adenylylcyclase 8 expression levels, glycosylation, nor dimerization status. In contrast, pentylamine, a substrate of Gα_h/TG2, was incorporated into adenylylcyclase 8 in a transglutaminase activity-dependent manner. Taking these results together, Gα_h/TG2 promotes cAMP production accompanied by a modification of adenylylcyclase 8 in glioma cells.
机译：Gα_h（或转谷氨酰胺酶2（TG2））是与G蛋白偶联受体缔合的非典型鸟嘌呤核苷酸结合蛋白。 TG2还具有转谷氨酰胺酶活性，可催化翻译后蛋白质的交联，形成ε-（γ-谷氨酰基）赖氨酸或（γ-谷氨酰基）多胺键。在这里，详细检查了Gα_h/ TG2在神经胶质细胞信号转导中的作用。在缺少Gα_h/ TG2的1321N1人星形细胞瘤细胞中，Gα_h/ TG2的过度表达导致β-肾上腺素受体激动剂异丙肾上腺素或腺苷酸环化酶激活剂forskolin刺激的cAMP蓄积增加。 TG2抑制剂ERW1069逆转了cAMP的增强作用。在表达内源性Gα_h/ TG2的大鼠C6胶质瘤细胞中，过表达Gα_h/ TG2-C277V的表达显着抑制了异丙肾上腺素或佛司可林诱导的cAMP积累，Gα_h/ TG2-C277V缺乏转谷氨酰胺酶活性，但不受Gα_h/ TG2抑制，但为显性负突变。 -S171E突变体，不能结合GTP / GDP。这些结果表明Gα_h/ TG2通过其转谷氨酰胺酶活性而不是通过其G蛋白活性来增强腺苷酸环化酶活性。 Gα_h/ TG2还增加了cAMP反应元件和白介素6启动子的活性，在两个神经胶质瘤细胞中都伴随有cAMP的缺失。由于腺苷酸环化酶8在cAMP产生中起主要作用，因此我们集中于Gα_h/ TG2对腺苷酸环化酶8的翻译后修饰。腺苷酸环化酶8在1321N1和C6细胞中均表达;然而，Gα_h/ TG2既不影响腺苷酸环化酶8的表达水平，糖基化作用，也不影响二聚化状态。相反，以转谷氨酰胺酶活性依赖性的方式将戊胺（Gα_h/ TG2的底物）掺入腺苷酸环化酶8中。综合这些结果，Gα_h/ TG2促进神经胶质瘤细胞中cAMP的产生并伴随腺苷酸环化酶8的修饰。

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