Dexamethasone-Induced Down-Regulation of Nerve Growth Factor Receptor p75NTR is Mediated by Glucocorticoid Type II Receptor in PC12 Cell Model

The Open Pharmacology Journal Pub Date : 2007-11-07 DOI:10.2174/1874143600701010019

S. Lecht, H. Arien-Zakay, R. Tabakman, Hao Jiang, D. Fink, P. Lazarovici

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引用次数: 3

Abstract

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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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

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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The Open Pharmacology Journal

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