Kerr J E, Beck S G, Handa R J
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
J Neuroendocrinol. 1996 Jun;8(6):439-47. doi: 10.1046/j.1365-2826.1996.04735.x.
Androgen, mineralocorticoid and glucocorticoid receptors (AR, MR and GR, respectively) are ligand-activated transcription factors that alter gene expression and have a wide variety of effects in the central nervous system. High levels of AR, MR and GR mRNA have been found in the CA1 pyramidal cell region of the rat hippocampus and all 3 of these proteins bind to a similar hormone response element in DNA suggesting the possibility of common receptor function or cross-talk between these receptors at the level of transcription. To begin to investigate this hypothesis, we examined the regulation of AR, MR and GR mRNA expression in the rat hippocampus following treatment with androgens in combination with gonadectomy and/or adrenalectomy. Three-month-old male Sprague-Dawley rats were either castrated for 3 weeks, castrated and immediately implanted with 2 Silastic capsules filled with the non-aromatizable androgen, dihydrotestosterone, or left gonadally intact. Four days prior to sacrifice, these animals were either adrenalectomized or sham operated. GR, MR and AR mRNA were measured in the hippocampal subfields using in situ hybridization. In the CA1 region, dihydrotestosterone treatment of castrates decreased GR mRNA levels to 69 percent of levels found in gonadally intact rats and prevented the adrenalectomy-induced increases in GR mRNA observed in the gonadally intact and castrated animals. No changes in GR mRNA were observed in the CA3 region or dentate gyrus, where AR expression is low or absent. There was no effect of androgen treatment on MR mRNA levels nor did gonadectomy or androgen replacement alter the increases in MR mRNA following adrenalectomy. AR mRNA levels in the CA1 region were unchanged across all treatment groups. In vitro binding studies revealed almost complete nuclear occupancy of hippocampal AR in dihydrotestosterone-treated castrates. No appreciable in vitro binding of dihydrotestosterone to hippocampal MR or GR (Ki approximately 1500 nM) was observed which suggests that androgen regulation of GR mRNA in the hippocampus is occurring through AR binding. These data demonstrate a functional similarity of androgens and glucocorticoids in the regulation of GR mRNA levels in an area where AR and GR are colocalized. Androgen-mediated downregulation of GR expression may prove to be an important event in the adaptive responses of CA1 pyramidal cells to hormonal stimuli.
雄激素、盐皮质激素和糖皮质激素受体（分别为AR、MR和GR）是配体激活的转录因子，可改变基因表达，并在中枢神经系统中具有多种作用。在大鼠海马体的CA1锥体细胞区域发现了高水平的AR、MR和GR mRNA，并且这三种蛋白质都与DNA中类似的激素反应元件结合，这表明这些受体在转录水平上可能具有共同的受体功能或相互作用。为了开始研究这一假设，我们研究了在联合去势和/或肾上腺切除术后用雄激素处理大鼠海马体后AR、MR和GR mRNA表达的调节情况。将3个月大的雄性Sprague-Dawley大鼠去势3周，或去势后立即植入2个装有不可芳香化雄激素双氢睾酮的硅胶胶囊，或保持性腺完整。在处死前4天，对这些动物进行肾上腺切除或假手术。使用原位杂交法测量海马亚区中的GR、MR和AR mRNA。在CA1区域，对去势大鼠进行双氢睾酮处理可使GR mRNA水平降至性腺完整大鼠中发现水平的69%，并阻止了在性腺完整和去势动物中观察到的肾上腺切除诱导的GR mRNA增加。在AR表达低或不存在的CA3区域或齿状回中未观察到GR mRNA的变化。雄激素处理对MR mRNA水平没有影响，去势或雄激素替代也未改变肾上腺切除术后MR mRNA的增加。所有处理组中CA1区域的AR mRNA水平均未改变。体外结合研究显示，在双氢睾酮处理的去势大鼠中，海马体AR几乎完全被核占据。未观察到双氢睾酮与海马体MR或GR有明显的体外结合（Ki约为1500 nM），这表明雄激素对海马体中GR mRNA的调节是通过AR结合发生。这些数据表明，在AR和GR共定位的区域，雄激素和糖皮质激素在调节GR mRNA水平方面具有功能相似性。雄激素介导的GR表达下调可能是CA1锥体细胞对激素刺激的适应性反应中的一个重要事件。
