Mittelman-Smith Melinda A, Wong Angela M, Kathiresan Anupama S Q, Micevych Paul E
David Geffen School of Medicine at University of California, Los Angeles, and Laboratory of Neuroendocrinology, Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90095.
Endocrinology. 2015 Jun;156(6):2162-73. doi: 10.1210/en.2014-1803. Epub 2015 Mar 2.
The neuropeptide kisspeptin is essential for sexual maturation and reproductive function. In particular, kisspeptin-expressing neurons in the anterior rostral periventricular area of the third ventricle are generally recognized as mediators of estrogen positive feedback for the surge release of LH, which stimulates ovulation. Estradiol induces kisspeptin expression in the neurons of the rostral periventricular area of the third ventricle but suppresses kisspeptin expression in neurons of the arcuate nucleus that regulate estrogen-negative feedback. To focus on the intracellular signaling and response to estradiol underlying positive feedback, we used mHypoA51 cells, an immortalized line of kisspeptin neurons derived from adult female mouse hypothalamus. mHypoA51 neurons express estrogen receptor (ER)-α, classical progesterone receptor (PR), and kisspeptin, all key elements of estrogen-positive feedback. As with kisspeptin neurons in vivo, 17β-estradiol (E2) induced kisspeptin and PR in mHypoA51s. The ERα agonist, 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, produced similar increases in expression, indicating that these events were mediated by ERα. However, E2-induced PR up-regulation required an intracellular ER, whereas kisspeptin expression was stimulated through a membrane ER activated by E2 coupled to BSA. These data suggest that anterior hypothalamic kisspeptin neurons integrate both membrane-initiated and classical nuclear estrogen signaling to up-regulate kisspeptin and PR, which are essential for the LH surge.
神经肽 kisspeptin 对性成熟和生殖功能至关重要。特别是，第三脑室嘴侧端室周区域中表达 kisspeptin 的神经元通常被认为是雌激素正反馈以促使促黄体生成素（LH）激增释放的介质，LH 激增可刺激排卵。雌二醇可诱导第三脑室嘴侧端室周区域神经元中 kisspeptin 的表达，但会抑制调节雌激素负反馈的弓状核神经元中 kisspeptin 的表达。为了聚焦于正反馈背后的细胞内信号传导及对雌二醇的反应，我们使用了 mHypoA51 细胞，这是一种源自成年雌性小鼠下丘脑的 kisspeptin 神经元永生化细胞系。mHypoA51 神经元表达雌激素受体（ER）-α、经典孕酮受体（PR）和 kisspeptin，这些都是雌激素正反馈的关键要素。与体内的 kisspeptin 神经元一样，17β-雌二醇（E2）可诱导 mHypoA51 细胞中 kisspeptin 和 PR 的表达。ERα 激动剂 1,3,5-三（4-羟苯基）-4-丙基-1H-吡唑可使表达产生类似的增加，表明这些事件是由 ERα 介导的。然而，E2 诱导的 PR 上调需要细胞内 ER，而 kisspeptin 的表达是通过与牛血清白蛋白偶联的 E2 激活的膜 ER 来刺激的。这些数据表明，下丘脑前部的 kisspeptin 神经元整合了膜起始的和经典的核雌激素信号传导，以上调 kisspeptin 和 PR，这对 LH 激增至关重要。
