Rapid corticosteroid-dependent regulation of mineralocorticoid receptor protein expression in rat brain
Rapid corticosteroid-dependent regulation of mineralocorticoid receptor protein expression in rat brain
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DOI：
10.1210/en.2002-220375
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发表时间：
2002-11-01
期刊：
影响因子：
4.8
通讯作者：
Spencer, RL
中科院分区：
文献类型：
--
作者：
Kalman, BA;Spencer, RL
皮质类固醇激素通过盐皮质激素受体(MR)和糖皮质激素受体(GR)调节神经功能的许多方面。虽然GR的表达受到内源性皮质类固醇激素的负调控，但对MR表达的自体调节研究较少，部分原因是受体结合分析的局限性，无法使用MR反应性抗体和Western印迹来测量MR的配体激活形式。我们检测了大鼠脑内相对MR蛋白的表达及其潜在的自我调节。是皮质类固醇引起的。我们发现，MR蛋白的表达受肾上腺类固醇激素的负调节。与GR相比，MR的调节速度更快，在肾上腺切除后12小时内MR蛋白显著增加，而GR水平在肾上腺切除后24小时内几乎没有增加。此外，与已发现同时受MR和GR调节的GR相反，肾上腺切除引起的MR增加可通过MR选择性激动剂醛固酮而不是GR选择性激动剂RU28362来预防。有趣的是，肾上腺切除大鼠经皮质酮急性处理后，全细胞MR蛋白在45min内显著降低，这表明配体诱导的MR快速降解长期高水平的皮质酮也导致MR蛋白水平显著低于肾上腺完整大鼠水平。这些结果对以前的研究有重要的意义，这些研究估计了体内不同水平的皮质酮占据MR的比例。这些研究比较了肾上腺完整的大鼠和肾上腺切除24小时的大鼠的有效MR结合水平，假设不同条件下总受体的表达没有差异。这些研究得出结论，MR几乎完全被循环中最低的皮质酮水平所占据。鉴于我们在肾上腺切除后24小时内观察到的MR蛋白增加了2到3倍，这些研究很可能大大高估了基础皮质酮水平较低的MR所占的比例。这些结果支持MR和GR可能参与糖皮质激素时相信号转导的前景。
Corticosteroid hormones regulate many aspects of neural function via mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Although GR expression is negatively regulated by endogenous corticosteroids, the autologous regulation of MR expression has been less well studied, partly due to limitations of receptor binding assays that cannot measure the ligand-activated form of MR. Using MR-reactive antibodies and Western blot, we examined relative MR protein expression in rat brain and its potential autoregulation. by corticosteroids. We found that MR protein expression is autoregulated in a negative fashion by adrenal steroids. Compared with GR, we see a more rapid regulation of MR, such that there is a substantial increase in MR protein within 12 h after adrenalectomy, whereas GR levels show very little increase until more than 24 h after adrenalectomy. Also, in contrast to GR, which has been found to be regulated by both MR and GR, adrenalectomy-induced increase in MR was prevented by treatment with the MR selective agonist, aldosterone, but not the GR selective agonist, RU28362. Interestingly, acute treatment of adrenalectomized rats with corticosterone produced a significant decrease in whole-cell MR protein within 45 min, suggesting ligand-induced rapid degradation of MR. Chronic high levels of corticosterone also produced a significant decrease in MR protein levels below adrenal-intact rat levels. These results have important implications for previous studies that estimated the proportion of MR that are occupied in vivo by various circulating levels of corticosterone. Those studies compared available MR binding levels in adrenal-intact rats with 24-h adrenalectomized rats, with the assumption that there were no differences between the various conditions in total receptor expression. Those studies concluded that MR is nearly fully occupied by even the lowest circulating corticosterone levels. Given the 2- to 3-fold increase in MR protein that we have observed within 24 h after adrenalectomy, it is likely that those studies significantly overestimated the proportion of MR that were occupied by low basal corticosterone levels. These results support the prospect that MR as well as GR can participate in the transduction of phasic corticosteroid signals.