Garcia James P, Guerriero Kathryn A, Keen Kim L, Kenealy Brian P, Seminara Stephanie B, Terasawa Ei
Wisconsin National Primate Research Center, Madison, Wisconsin 53715.
Reproductive Endocrine Unit and the Harvard Reproductive Sciences Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
Endocrinology. 2017 Oct 1;158(10):3269-3280. doi: 10.1210/en.2017-00500.
Loss-of-function or inactivating mutations in the genes coding for kisspeptin and its receptor (KISS1R) or neurokinin B (NKB) and the NKB receptor (NK3R) in humans result in a delay in or the absence of puberty. However, precise mechanisms of kisspeptin and NKB signaling in the regulation of the pubertal increase in gonadotropin-releasing hormone (GnRH) release in primates are unknown. In this study, we conducted a series of experiments infusing agonists and antagonists of kisspeptin and NKB into the stalk-median eminence, where GnRH, kisspeptin, and NKB neuroterminal fibers are concentrated, and measuring GnRH release in prepubertal and pubertal female rhesus monkeys. Results indicate that (1) similar to those previously reported for GnRH stimulation by the KISS1R agonist (i.e., human kisspeptin-10), the NK3R agonist senktide stimulated GnRH release in a dose-responsive manner in both prepubertal and pubertal monkeys; (2) the senktide-induced GnRH release was blocked in the presence of the KISS1R antagonist peptide 234 in pubertal but not prepubertal monkeys; and (3) the kisspeptin-induced GnRH release was blocked in the presence of the NK3R antagonist SB222200 in the pubertal but not prepubertal monkeys. These results are interpreted to mean that although, in prepubertal female monkeys, kisspeptin and NKB signaling to GnRH release is independent, in pubertal female monkeys, a reciprocal signaling mechanism between kisspeptin and NKB neurons is established. We speculate that this cooperative mechanism by the kisspeptin and NKB network underlies the pubertal increase in GnRH release in female monkeys.
人类中编码 kisspeptin 及其受体（KISS1R）、神经激肽 B（NKB）和 NKB 受体（NK3R）的基因发生功能丧失或失活突变会导致青春期延迟或缺失。然而，在灵长类动物中，kisspeptin 和 NKB 信号传导在调节促性腺激素释放激素（GnRH）青春期释放增加方面的确切机制尚不清楚。在本研究中，我们进行了一系列实验，将 kisspeptin 和 NKB 的激动剂和拮抗剂注入柄-正中隆起，GnRH、kisspeptin 和 NKB 神经终末纤维在此处集中，并测量青春期前和青春期雌性恒河猴的 GnRH 释放。结果表明：（1）与先前报道的 KISS1R 激动剂（即人 kisspeptin-10）刺激 GnRH 释放的情况类似，NK3R 激动剂 senktide 在青春期前和青春期猴子中均以剂量反应方式刺激 GnRH 释放；（2）在青春期猴子中，KISS1R 拮抗剂肽 234 存在时，senktide 诱导的 GnRH 释放被阻断，而在青春期前猴子中未被阻断；（3）在青春期猴子中，NK3R 拮抗剂 SB222200 存在时，kisspeptin 诱导的 GnRH 释放被阻断，而在青春期前猴子中未被阻断。这些结果被解释为，虽然在青春期前雌性猴子中，kisspeptin 和 NKB 向 GnRH 释放的信号传导是独立的，但在青春期雌性猴子中，kisspeptin 和 NKB 神经元之间建立了一种相互信号传导机制。我们推测，kisspeptin 和 NKB 网络的这种协同机制是雌性猴子青春期 GnRH 释放增加的基础。
