Laboratory of Integrative Brain Sciences, Department of Biology, Waseda University, Center for Medical Life Science of Waseda University, Tokyo, Japan.
Endocrinology. 2010 May;151(5):2211-22. doi: 10.1210/en.2009-1229. Epub 2010 Mar 10.
We recently found that the Japanese red-bellied newt, Cynops pyrrhogaster, actively produces 7alpha-hydroxypregnenolone, a previously undescribed amphibian neurosteroid. 7alpha-Hydroxypregnenolone stimulates locomotor activity of male newts. Locomotor activity of male newts increases during the breeding period as in other wild animals, but the molecular mechanism for such a change in locomotor activity is poorly understood. Here we show that the adenohypophyseal hormone prolactin (PRL) stimulates 7alpha-hydroxypregnenolone synthesis in the brain, thus increasing locomotor activity of breeding male newts. In this study, cytochrome P450(7alpha) (CYP7B), a steroidogenic enzyme catalyzing the formation of 7alpha-hydroxypregnenolone, was first identified to analyze seasonal changes in 7alpha-hydroxypregnenolone synthesis. Only males exhibited marked seasonal changes in 7alpha-hydroxypregnenolone synthesis and CYP7B expression in the brain, with a maximum level in the spring breeding period when locomotor activity of males increases. Subsequently we identified PRL as a key component of the mechanism regulating 7alpha-hydroxypregnenolone synthesis. Hypophysectomy decreased 7alpha-hydroxypregnenolone synthesis in the male brain, whereas administration of PRL but not gonadotropins to hypophysectomized males caused a dose-dependent increase in 7alpha-hydroxypregnenolone synthesis. To analyze the mode of PRL action, CYP7B and the receptor for PRL were localized in the male brain. PRL receptor was expressed in the neurons expressing CYP7B in the magnocellular preoptic nucleus. Thus, PRL appears to act directly on neurosteroidogenic magnocellular preoptic nucleus neurons to regulate 7alpha-hydroxypregnenolone synthesis, thus inducing seasonal locomotor changes in male newts. This is the first report describing the regulation of neurosteroidogenesis in the brain by an adenohypophyseal hormone in any vertebrate.
我们最近发现，日本红腹蝾螈（ Cynops pyrrhogaster ）积极产生 7α-羟基孕烯醇酮，这是一种以前未被描述的两栖动物神经甾体。7α-羟基孕烯醇酮刺激雄性蝾螈的运动活性。与其他野生动物一样，雄性蝾螈在繁殖期的运动活性增加，但这种运动活性变化的分子机制知之甚少。在这里，我们表明腺垂体激素催乳素（PRL）刺激脑内 7α-羟基孕烯醇酮的合成，从而增加繁殖期雄性新蝾螈的运动活性。在这项研究中，首次鉴定细胞色素 P450（7α）（CYP7B），一种催化 7α-羟基孕烯醇酮形成的甾体生成酶，以分析 7α-羟基孕烯醇酮合成的季节性变化。只有雄性表现出脑内 7α-羟基孕烯醇酮合成和 CYP7B 表达的明显季节性变化，当雄性的运动活性增加时，其在春季繁殖期达到最高水平。随后，我们确定 PRL 是调节 7α-羟基孕烯醇酮合成的机制的关键组成部分。垂体切除术降低了雄性脑中的 7α-羟基孕烯醇酮合成，而 PRL 而不是促性腺激素给药于垂体切除的雄性中引起 7α-羟基孕烯醇酮合成的剂量依赖性增加。为了分析 PRL 作用的模式，将 CYP7B 和 PRL 受体定位于雄性脑中。PRL 受体在大细胞视前核中表达 CYP7B 的神经元中表达。因此，PRL 似乎直接作用于神经甾体生成的大细胞视前核神经元以调节 7α-羟基孕烯醇酮合成，从而诱导雄性新蝾螈的季节性运动变化。这是描述任何脊椎动物中腺垂体激素对脑内神经甾体生成的调节的第一个报告。
