Kisspeptin Signaling Is Indispensable for Neurokinin B, but not Glutamate, Stimulation of Gonadotropin Secretion in Mice
Kisspeptin Signaling Is Indispensable for Neurokinin B, but not Glutamate, Stimulation of Gonadotropin Secretion in Mice
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DOI：
10.1210/en.2011-1260
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发表时间：
2012-01-01
期刊：
影响因子：
4.8
通讯作者：
Tena-Sempere, Manuel
中科院分区：
文献类型：
--
作者：
Garcia-Galiano, David;Schenau, Dorette van Ingen;Tena-Sempere, Manuel
Kisspeptins(KP)是Kiss1基因的产物，通过GPR54有效地刺激GnRH的分泌，作为促性腺激素轴的其他调节信号的中介。GPR54和/或Kiss1失活的小鼠模型已经被用来研究Kp在促性腺激素分泌的中枢控制中的作用；然而，在可用的转基因株系中，已经检测到表型和激素的差异。我们报告了一系列雄性小鼠的神经内分泌分析，该模型是由loxP-Gpr54/鱼精蛋白-Cre双突变系杂合杂交产生的一种新的Gpr54基因敲除(KO)模型。GPR54缺失的男性表现出严重的低促性腺激素减退症，但对GnRH仍有很强的反应。在GPR54基因缺失的小鼠中，对离子型谷氨酸受体激动剂N-甲基-D-天冬氨酸的促性腺反应减弱，但持续。相反，在没有GPR54信号的情况下，代谢性谷氨酸受体激活后的促黄体生成素分泌完全保持不变。Gpr54 KO小鼠在侧脑室注射甘丙肽样肽或RF9后，也观察到可检测到的促黄体生成素反应，虽然减少了，但仍有反应。相反，神经激肽B激动剂(NKB；Kiss1神经元的共同递质)的刺激作用在Gpr54 KO男性中被完全取消。缺乏KP信号也消除了黄体生成素对睾酮停用的反馈反应。然而，在性腺切除的GPR54KO男性中，检测到残留但持续的FSH升高，在这种情况下，睾酮替代未能完全抑制循环中的FSH水平。总之，我们的研究为GnRH分泌的几个关键调节因子，如谷氨酸、甘丙肽样肽和睾酮的依赖于KP的作用与非依赖作用的相对重要性提供了新的证据。此外，我们的数据首次证明了Kp信号在介导NKB对促黄体生成素分泌的刺激效应中起着不可或缺的作用，从而支持了NKB对GnRH神经元的作用是通过其调节Kiss1神经元输出的能力间接介导的假说。(内分泌学153：316-328,2012)
Kisspeptins (Kp), products of the Kiss1 gene that act via Gpr54 to potently stimulate GnRH secretion, operate as mediators of other regulatory signals of the gonadotropic axis. Mouse models of Gpr54 and/or Kiss1 inactivation have been used to address the contribution of Kp in the central control of gonadotropin secretion; yet, phenotypic and hormonal differences have been detected among the transgenic lines available. We report here a series of neuroendocrine analyses in male mice of a novel Gpr54 knockout (KO) model, generated by heterozygous crossing of a loxP-Gpr54/Protamine-Cre double mutant line. Gpr54-null males showed severe hypogonadotropic hypogonadism but retained robust responsiveness to GnRH. Gonadotropic responses to the agonist of ionotropic glutamate receptors, N-methyl-D-aspartate, were attenuated, but persisted, in Gpr54-null mice. In contrast, LH secretion after activation of metabotropic glutamate receptors was totally preserved in the absence of Gpr54 signaling. Detectable, albeit reduced, LH responses were also observed in Gpr54 KO mice after intracerebroventricular administration of galanin-like peptide or RF9, putative antagonist of neuropeptide FF receptors for the mammalian ortholog of gonadotropin-inhibiting hormone. In contrast, the stimulatory effect of senktide, agonist of neurokinin B (NKB; cotransmitter of Kiss1 neurons), was totally abrogated in Gpr54 KO males. Lack of Kp signaling also eliminated feedback LH responses to testosterone withdrawal. However, residual but sustained increases of FSH were detected in gonadectomized Gpr54 KO males, in which testosterone replacement failed to fully suppress circulating FSH levels. In sum, our study provides novel evidence for the relative importance of Kp-dependent vs. -independent actions of several key regulators of GnRH secretion, such as glutamate, galanin-like peptide, and testosterone. In addition, our data document for the first time the indispensable role of Kp signaling in mediating the stimulatory effects of NKB on LH secretion, thus supporting the hypothesis that NKB actions on GnRH neurons are indirectly mediated via its ability to regulate Kiss1 neuronal output. (Endocrinology 153: 316-328, 2012)