Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals
Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals
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DOI：
10.1210/en.2007-1487
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Colledge, William H.
中科院分区：
文献类型：
--
作者：
de Tassigny, Xavier d'Anglemont;Fagg, Lisa A.;Colledge, William H.
G 蛋白偶联受体 GPR54 及其肽配体 Kisspeptin (Kp) 对于哺乳动物生殖功能的诱导和维持至关重要。 GPR54由GnRH神经元表达，并直接被Kp激活以刺激GnRH释放。我们假设 Kp 可能能够作用于位于下丘脑内侧基底层 (MBH) 区域的 GnRH 神经末梢。为了检验这一假设，我们使用 Kp 攻击的 MBH 外植体进行器官型培养，然后通过 RIA 检测释放到培养基中的 GnRH。 Kp 刺激 1 小时诱导野生型雄性 MBH 以剂量依赖性方式释放 GnRH，而在从 Gpr54 null 小鼠分离的 MBH 外植体中则不会发生这种情况。连续 Kp 刺激导致 GnRH 持续释放 4 小时，随后 GnRH 释放减少，表明 GPR54 活性脱敏。河豚毒素不会改变 Kp 诱导的 GnRH 释放，表明 Kp 可以直接作用于 GnRH 神经末梢。为了将 Gpr54 表达定位在 MBH 内，我们使用了转基因小鼠，其中 Gpr54 表达用 IRES-LacZ 报告基因标记，并且可以通过 β-半乳糖苷酶染色来可视化。在正中隆起之外的结节部检测到 Gpr54 表达。总之，我们的结果为 Kp 对小鼠 MBH 中 GnRH 神经末梢的有效刺激作用提供了证据。这项研究提出了 Kp 作用于 GnRH 神经元的新点。
The G protein-coupled receptor GPR54, and its peptide ligand kisspeptin (Kp), are crucial for the induction and maintenance of mammalian reproductive function. GPR54 is expressed by GnRH neurons and is directly activated by Kp to stimulate GnRH release. We hypothesized that Kp may be able to act at the GnRH nerve terminals located in the mediobasal hypothalamus (MBH) region. To test this hypothesis, we used organotypic culture of MBH explants challenged with Kp, followed by RIA to detect GnRH released into the cultured medium. Kp stimulation for 1 h induced GnRH release from wildtype male MBH in a dose-dependent manner, whereas this did not occur in MBH explants isolated from Gpr54 null mice. Continuous Kp stimulation caused a sustained GnRH release for 4 h, followed by a decrease of GnRH release, suggesting a desensitization of GPR54 activity. Tetrodotoxin did not alter the Kp-induced GnRH release, indicating that Kp can act directly at the GnRH nerve terminals. To localize Gpr54 expression within the MBH, we used transgenic mice, in which Gpr54 expression is tagged with an IRES-LacZ reporter gene and can be visualized by beta-galactosidase staining. Gpr54 expression was detected outside of the median eminence, in the pars tuberalis. In conclusion, our results provide evidence for a potent stimulating effect of Kp at GnRH nerve terminals in the MBH of the mouse. This study suggests a new point at which Kp can act on GnRH neurons.