糖皮质激素II型受体介导地塞米松诱导PC12细胞模型中神经生长因子受体p75NTR的下调

S. Lecht, H. Arien-Zakay, R. Tabakman, Hao Jiang, D. Fink, P. Lazarovici
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引用次数: 3

摘要

我们建立了PC12克隆的神经元模型,以研究神经营养因子与药物之间相互作用的机制。用糖皮质激素激动剂药物地塞米松(Dex)慢性治疗PC12细胞,可导致125 I-NGF选择性结合减少50%,并降低NGF受体p75 NTR mRNA和蛋白水平,提示其转录机制。这种p75 NTR的下调被谷氨酸皮质激素II型受体(GR-2) RU-38486拮抗,而不被矿化皮质激素受体RU-28318拮抗。这一过程与NGF受体TrkA的自磷酸化增加有关。用Dex慢性处理PC12 20小时后,ngf诱导的细胞增殖消失,96小时后,神经突伸长被抑制45%。RU-38486可阻断dex诱导的PC12细胞从多巴胺能表型向去甲肾上腺素能表型的转变。Dex诱导的p75 NTR受体下调是由GR-2介导的,与NGF诱导的增殖破坏有关
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Dexamethasone-Induced Down-Regulation of Nerve Growth Factor Receptor p75NTR is Mediated by Glucocorticoid Type II Receptor in PC12 Cell Model
PC12 clones are established neuronal models to investigate mechanisms involved in the cross-talk between the neurotrophins and drugs. Chronic treatment of PC12 cells with the glucocorticoid agonist drug, dexamethasone (Dex), elicited a 50% decrease in the selective binding of 125 I-NGF along with a reduction in the NGF receptor p75 NTR mRNA and protein levels, suggesting a transcriptional mechanism. This down regulation of p75 NTR was antagonized by the glu- cocorticoid type II receptor (GR-2), RU-38486 but not by the minerallocorticoid receptor, RU-28318, antagonists. This process was associated with increased autophosphorylation of the NGF receptor, TrkA. Chronic treatment of PC12 with Dex abolished the NGF-induced proliferation of the cells after 20 hours and inhibited by 45% the neurite elongation after 96 hours. RU-38486 blocked Dex-induced shift of PC12 cells from dopaminergic to noradrenergic phenotype. Dex- induced down regulation of p75 NTR receptor is mediated by GR-2 and is correlated with disruption of NGF induced prolif-
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