Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37604, USA.
J Neurochem. 2010 Apr;113(1):105-16. doi: 10.1111/j.1471-4159.2010.06587.x. Epub 2010 Jan 13.
Glucocorticoids affect cellular and molecular events in brains by modulating the expression of many genes during stress. In the present study, we examined the regulatory effect of corticosterone on the expression and function of the norepinephrine transporter (NET) in vitro. The results show that exposure of SK-N-BE(2)C cells to corticosterone for 14 days significantly increased mRNA (up to 43%) and protein (up to 71%) levels of NET in the concentration-dependent manner. Longer exposure (21 days) resulted in greater increases in the levels of mRNAs (up to about 160%) and proteins (up to about 250%) of the NET. The up-regulatory effect of corticosterone on NET expression lasted a persistent period after cessation of exposure. Associated with the corticosterone-induced enhancement in NET expression, there was a parallel increase in the uptake of [(3)H]norepinephrine by SK-N-BE(2)C cells. Increased NET expression and function were abolished after exposure of cells to corticosterone in combination with mifepristone or spironolactone, two specific antagonists of corticosteroid receptors. This is consistent with the hypothesis that corticosterone-induced NET up-regulation is mediated by corticosteroid receptors. Nevertheless, there was no synergistic effect for a combination of both corticosteroid receptor antagonists. A similar up-regulation of NET protein levels was also observed after exposing PC12 cells to corticosterone. The present findings demonstrate that corticosterone up-regulates the expression and function of NET in vitro, indicating the action of corticosterone on the noradrenergic phenotype may play an important role in the correlation between stress and the development of depression.
糖皮质激素通过调节应激时许多基因的表达来影响大脑中的细胞和分子事件。在本研究中，我们研究了皮质酮对 SK-N-BE(2)C 细胞体外培养中去甲肾上腺素转运体（NET）表达和功能的调节作用。结果表明，皮质酮处理 SK-N-BE(2)C 细胞 14 天，NET 的 mRNA（增加 43%）和蛋白（增加 71%）水平呈浓度依赖性增加。较长时间（21 天）的暴露导致 NET 的 mRNA（增加约 160%）和蛋白（增加约 250%）水平增加更大。皮质酮对 NET 表达的上调作用在停止暴露后持续存在。与皮质酮诱导的 NET 表达增强相关，SK-N-BE(2)C 细胞对 [(3)H]去甲肾上腺素的摄取也呈平行增加。细胞暴露于皮质酮与米非司酮或螺内酯联合后，NET 表达和功能增加被消除，米非司酮和螺内酯是两种皮质激素受体的特异性拮抗剂。这与皮质酮诱导的 NET 上调是由皮质激素受体介导的假说一致。然而，两种皮质激素受体拮抗剂的联合使用没有协同作用。PC12 细胞暴露于皮质酮后，NET 蛋白水平也出现类似的上调。本研究结果表明，皮质酮在体外上调 NET 的表达和功能，表明皮质酮对去甲肾上腺素能表型的作用可能在应激与抑郁发生的相关性中起重要作用。
