Glucocorticoids inhibit stress-induced phosphorylation of CREB in corticotropin-releasing hormone neurons of the hypothalamic paraventricular nucleus.
Glucocorticoids inhibit stress-induced phosphorylation of CREB in corticotropin-releasing hormone neurons of the hypothalamic paraventricular nucleus.
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DOI：
10.1159/000127224
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发表时间：
1997-07
影响因子：
4.1
通讯作者：
G. Légrádi;D. Holzer;L. Kapcala;R. Lechan
中科院分区：
文献类型：
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作者：
G. Légrádi;D. Holzer;L. Kapcala;R. Lechan
促肾上腺皮质激素释放激素 (CRH) 基因在其启动子区域包含完美的回文基序，允许结合环磷酸腺苷反应元件结合蛋白 CREB。由于先前的研究表明 CRH 基因可以被环磷酸腺苷激活，因此我们确定了糖皮质激素对下丘脑室旁核中产生 CRH 的神经元的应激和反馈抑制是否可以通过 CREB 磷酸化的变化来介导。 CREB 抗血清和磷酸化 CREB Ser133 (PCREB)（CREB 的活性磷酸化形式）用于大鼠脑的免疫组织化学研究。在非应激动物中，CREB 免疫染色仅限于整个下丘脑中普遍存在的细胞核，而 PCREB 免疫染色离散地定位于大细胞神经元中，并且仅位于室旁核内侧小细胞分区中的少数细胞中。乙醚和处理应激显着增加了小细胞细分中 PCREB 标记的神经元数量。 CRH 抗血清双重免疫标记显示，应激动物中大多数促垂体 CRH 神经元表达 PCREB。全身给予地塞米松（100微克/天）2.5天后，在乙醚或处理应激后，产生CRH的细小细胞神经元中的PCREB免疫染色完全消失。地塞米松对 CREB 免疫染色无明显影响。这些结果表明，糖皮质激素抑制促垂体 CRH 神经元中的 CREB 磷酸化，并表明防止 CREB 磷酸化是糖皮质激素反馈抑制 CRH 生物合成的可能机制。
The corticotropin-releasing hormone (CRH) gene contains a perfect palindromic motif in its promoter region that allows binding of the cyclic adenosine monophosphate response element binding protein, CREB. Since previous studies suggest that the CRH gene can be activated by cyclic adenosine monophosphate, we determined whether stress and feedback inhibition by glucocorticoids in CRH-producing neurons in the hypothalamic paraventricular nucleus could be mediated by changes in the phosphorylation of CREB. Antisera to CREB and phospho-CREB Ser133 (PCREB), the active phosphorylated form of CREB, were used for immunohistochemical studies on rat brain. In nonstressed animals CREB immunostaining was confined to the nucleus of cells ubiquitously throughout the hypothalamus, while PCREB immunostaining was discretely localized in magnocellular neurons and only a few cells in the medial parvocellular subdivision of the paraventricular nucleus. Ether and handling stress markedly increased the number of PCREB-labeled neurons in the parvocellular subdivision. Double immunolabeling with CRH antiserum revealed that the majority of hypophysiotropic CRH neurons in stressed animals expressed PCREB. Following systemic administration of dexamethasone (100 micrograms/day) for 2.5 days, PCREB immunostaining was completely abolished in parvocellular CRH-producing neurons after ether or handling stress. Dexamethasone had no apparent effect on CREB immunostaining. These results demonstrate that glucocorticoids suppress CREB phosphorylation in hypophysiotropic CRH neurons and suggest that prevention of CREB phosphorylation is a possible mechanism for feedback inhibition of CRH biosynthesis by glucocorticoids.