Differential effects of antidepressants on dexamethasone-induced nuclear translocation and expression of glucocorticoid receptor
Differential effects of antidepressants on dexamethasone-induced nuclear translocation and expression of glucocorticoid receptor
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DOI：
10.1016/j.brainres.2006.08.029
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发表时间：
2006-10-30
期刊：
影响因子：
2.9
通讯作者：
Watanabe, Yoshifumi
中科院分区：
文献类型：
--
作者：
Funato, Hiromasa;Kobayashi, Ayumi;Watanabe, Yoshifumi
糖皮质激素受体（GR）是下丘脑-垂体-肾上腺（HPA）轴的关键调节因子。情绪障碍患者经常在这个轴上表现出异常。虽然抗抑郁药的临床获益与HPA轴负反馈增强导致的HPA活性正常化有关，但其确切机制尚不清楚。为了研究抗抑郁药对GR易位到细胞核中的影响，我们对SY 5 Y细胞进行了延时观察，该细胞已瞬时转染了表达绿色荧光蛋白（GFP）标记的GR α的质粒。氯硝帕明和地昔帕明促进地塞米松（Dex）诱导的GFP-GR α核转位。维拉帕米（一种膜类固醇转运蛋白的抑制剂）的共孵育对Dex和氯丙咪嗪诱导的GFP-GR α核转位几乎没有或没有累加效应。在没有Dex的情况下，抗抑郁药不会诱导GFP-GR α易位到细胞核中。使用实时PCR，我们研究了抗抑郁药对剪接异构体的影响。GR，GR α，GR β在SY 5 Y和Jurkat细胞中的表达。与帕罗西汀和地昔帕明孵育48小时和7天增加GR α的表达，而GR β的表达保持稳定。抗抑郁药没有改变与GR转录物选择性剪接相关的SRp 30 c的表达。因此，抗抑郁药对GR的易位和表达发挥不同的作用，以增强GR信号传导。(c)2006 Elsevier B. V.保留所有权利。
The glucocorticoid receptor (GR) is a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Mood disorder patients often exhibit abnormalities in this axis. Although the clinical benefit of antidepressants is associated with the normalization of the disturbed HPA activity by enhanced negative feedback of the HPA axis, the precise mechanism remains unknown. In order to examine the effect of antidepressants on the translocation of GR into the nucleus, we performed time-lapse observation on SY5Y cells that had been transiently transfected with plasmids expressing the green fluorescence protein (GFP)-tagged GR alpha. Clornipramine and desipramine facilitated dexamethasone (Dex)-induced GFP-GR alpha nuclear translocation. Coincubation of verapamil, an inhibitor of membrane steroid transporters, showed little or no additive effect on GFP-GR alpha nuclear translocation induced by both Dex and clomipramine. In the absence of Dex, antidepressants did not induce the translocation of GFP-GR alpha into the nucleus. Using real-time PCR, we examined the effect of antidepressants on splicing isoform. of GR, GR alpha, and GR beta in SY5Y and jurkat cells. Incubation with paroxetine and desipramine for 48 h and 7 days increased GR alpha expression, whereas the expression of GR beta remained stable. Antidepressants did not alter the expression of SRp30c that is associated with alternative splicing of GR transcript. Thus, antidepressants exert differential effects on the translocation and expression of GR to enhance GR signaling. (c) 2006 Elsevier B.V. All rights reserved.