Dungan Heather M, Clifton Donald K, Steiner Robert A
Department of Physiology and Biophysics, Health Sciences Building, G-424, School of Medicine, University of Washington, Box 357290, Seattle, Washington 98195-7290, USA.
Endocrinology. 2006 Mar;147(3):1154-8. doi: 10.1210/en.2005-1282. Epub 2005 Dec 22.
The Kiss1 gene encodes a family of peptides called kisspeptins, which bind to the G protein-coupled receptor GPR54. Kisspeptin(s) and its receptor are expressed in the forebrain, and the discovery that mice and humans lacking a functional GPR54 fail to undergo puberty and exhibit hypogonadotropic hypogonadism implies that kisspeptin signaling plays an essential role in reproduction. Studies in several mammalian species have shown that kisspeptins stimulate the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain after the activation of GPR54, which is expressed by GnRH neurons. Kisspeptin is expressed abundantly in the arcuate nucleus (Arc) and the anteroventral periventricular nucleus (AVPV) of the forebrain. Both estradiol and testosterone regulate the expression of the Kiss1 gene in the Arc and AVPV; however, the response of the Kiss1 gene to these steroids is exactly opposite between these two nuclei. Estradiol and testosterone down-regulate Kiss1 mRNA in the Arc and up-regulate its expression in the AVPV. Thus, kisspeptin neurons in the Arc may participate in the negative feedback regulation of gonadotropin secretion, whereas kisspeptin neurons in the AVPV may contribute to generating the preovulatory gonadotropin surge in the female. Hypothalamic levels of Kiss1 and GPR54 mRNA increase dramatically at puberty, suggesting that kisspeptin signaling could mediate the neuroendocrine events that trigger the onset of puberty. Together, these observations demonstrate that kisspeptin-GPR54 signaling in the brain serves as an important conduit for controlling GnRH secretion in the developing and adult animal.
Kiss1基因编码一类名为亲吻素的肽，亲吻素可与G蛋白偶联受体GPR54结合。亲吻素及其受体在前脑表达，缺乏功能性GPR54的小鼠和人类无法进入青春期并表现出低促性腺激素性性腺功能减退，这一发现表明亲吻素信号在生殖过程中起着至关重要的作用。对几种哺乳动物的研究表明，激活由促性腺激素释放激素（GnRH）神经元表达的GPR54后，亲吻素通过刺激前脑释放GnRH来刺激垂体促性腺激素的分泌。亲吻素在前脑的弓状核（Arc）和室周前腹核（AVPV）中大量表达。雌二醇和睾酮均可调节Arc和AVPV中Kiss1基因的表达；然而，Kiss1基因对这两种类固醇的反应在这两个核中恰好相反。雌二醇和睾酮下调Arc中的Kiss1 mRNA并上调其在AVPV中的表达。因此，Arc中的亲吻素神经元可能参与促性腺激素分泌的负反馈调节，而AVPV中的亲吻素神经元可能有助于在雌性动物中产生排卵前促性腺激素高峰。青春期时下丘脑Kiss1和GPR54 mRNA水平显著升高，这表明亲吻素信号可能介导触发青春期开始的神经内分泌事件。综上所述，这些观察结果表明，大脑中的亲吻素-GPR54信号是控制发育中和成年动物GnRH分泌的重要途径。
