Direct pituitary effects of kisspeptin:: Activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion
Direct pituitary effects of kisspeptin:: Activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion
复制标题
DOI：
10.1111/j.1365-2826.2007.01558.x
复制
发表时间：
2007-07-01
影响因子：
3.2
通讯作者：
Castano, J. P.
中科院分区：
文献类型：
--
作者：
Gutierrez-Pascual, E.;Martinez-Fuentes, A. J.;Castano, J. P.
最近的证据表明，KiSS-1基因的产物Kispeptins及其受体GPr54是神经内分泌控制生殖的关键元件，它们主要通过调节下丘脑的促性腺激素释放激素(GnRH)发挥作用。相反，尽管早些时候的报道显示GPR54在脑下垂体中表达，但Kispeptins在这个腺体中的潜在生理作用仍然难以捉摸。为了阐明这一问题，我们采用体外培养的大鼠垂体细胞来检测KiSS-1和GPR54的表达，并监测KISS-10在体外刺激促性腺激素细胞的钙反应和诱导黄体生成素(LH)分泌的能力。结果表明，GPR54和KiSS-1在青春期雄性和雌性大鼠的脑垂体中均有表达。此外，Kispeptin-10可诱导约10%的雄性大鼠垂体细胞内游离钙离子浓度([Ca~(2+)](I))升高。有趣的是，Kispeptin反应的细胞不仅包括促性腺激素细胞，其中[Ca~(2+)](I)升高了62.8+/-16.0%，而且还包括生长激素细胞，其中Kispeptin诱导了60.3+/-5.5%的[Ca~(2+)](I)升高。因此，随着Kispeptin-10浓度的增加，分散的垂体细胞可诱导剂量相关的促黄体生成素和生长激素(GH)分泌反应，但其幅度分别低于初级调节剂GnRH和GH释放激素。其中，10(-8)M的Kispeptin可显著增加黄体生成素的释放(雄性和雌性大鼠分别为218.7+/-23.6%和180.4+/-7.2%)，并最大程度地刺激GH的分泌(雄性和雌性分别为181.9+/-14.9%和260.2+/-15.9%)。此外，在雄性大鼠垂体细胞短期孵育后，观察到Kispeptin和GnRH诱导的促黄体生成素反应的适度总和。总之，我们的研究结果提供了确凿的证据，表明Kispeptins对青春期前后的雄性和雌性大鼠都有直接的脑下垂体作用，并提示了一种可能的自分泌/旁分泌作用模式。Kispeptins潜在的新作用(即直接调节脑下垂体促性腺激素和生长激素轴)的确切相关性和潜在机制值得进一步分析。
Recent, compelling evidence indicates that kisspeptins, the products of KiSS-1 gene, and their receptor GPR54, represent key elements in the neuroendocrine control of reproduction, and that they act primarily by regulating gonadotrophin-releasing hormone (GnRH) secretion at the hypothalamus. Conversely, and despite earlier reports showing GPR54 expression in the pituitary, the potential physiological roles of kisspeptins at this gland have remained elusive. To clarify this issue, cultures of rat pituitary cells were used to evaluate expression of KiSS-1 and GPR54, and to monitor the ability of kisspeptin-10 to stimulate Ca2+ responses in gonadotrophs and to elicit luteinising hormone (LH) secretion in vitro. The results obtained show that both GPR54 and KiSS-1 are expressed in the pituitary of peripubertal male and female rats. Moreover, kisspeptin-10 induced a rise in free cytosolic Ca2+ concentration ([Ca2+](i)) in approximately 10% of male rat pituitary cells. Intriguingly, kisspeptin-responsive cells included not only gonadotrophs, in which a 62.8 +/- 16.0%[Ca2+](i) rise was observed, but also somatotrophs, wherein kisspeptin induced a 60.3 +/- 5.5%[Ca2+](i) increase. Accordingly, challenge of dispersed pituitary cells with increasing kisspeptin-10 concentrations induced dose-related LH and growth hormone (GH) secretory responses, which were nevertheless of lower magnitude than those evoked by the primary regulators GnRH and GH-releasing hormone, respectively. In particular, 10(-8) M kisspeptin caused maximal increases in LH release (218.7 +/- 23.6% and 180.4 +/- 7.2% in male and female rat pituitary cells, respectively), and also stimulated maximally GH secretion (181.9 +/- 14.9% and 260.2 +/- 15.9% in male and female rat pituitary cells, respectively). Additionally, moderate summation of kisspeptin- and GnRH-induced LH responses was observed after short-term incubation of male rat pituitary cells. In conclusion, our results provide unequivocal evidence that kisspeptins exert direct pituitary effects in peripubertal male and female rats and suggest a possible autocrine/paracrine mode of action. The precise relevance and underlying mechanisms of this potential new actions of kisspeptins (i.e. the direct modulation of gonadotrophic and somatotrophic axis at the pituitary) deserve further analysis.