The hypothalamic hormone GnRH is a central driver of pituitary gonadotropin secretion, controlling pulsatile gonadotropin secretion, modulating gonadal steroid feedback, and bringing about full fertility in the adult. Thus, understanding GnRH neuronal regulation is essential to understanding the neurohumoral control of human reproduction. Genetic tools were used in patients with GnRH deficiency (i.e. idiopathic hypogonadotropic hypogonadism), a clinical syndrome that results from the failure of a normal pattern of pulsatile GnRH, to discover upstream modulators of GnRH secretion (1). In 2003, homozygosity mapping of two consanguineous pedigrees led to the identification of loss of function mutations in KISS1R (a G protein coupled receptor) by two groups (2, 3). In parallel, the Kiss1r(-/-) mouse was shown to be a phenocopy of the human GnRH-deficient state, demonstrating that the function of KISS1R/Kiss1r is conserved across mammalian species (4). Just before these human genetic discoveries, the ligand for kisspeptin-1 receptor [KISS1R; also known as G protein coupled receptor 54 (GPR54)], was discovered to be kisspeptin. Soon thereafter a large array of experimental studies began assembling genetic, expression, physiologic, transgenic, knockdown, and electrophysiological data to characterize the physiology of kisspeptin and its seminal role in modulating GnRH release.

译文

下丘脑激素GnRH是垂体促性腺激素分泌的主要驱动因素,控制搏动性促性腺激素分泌,调节性腺类固醇反馈,并在成年人中实现完全生育。因此,了解GnRH神经元调节对于理解人类生殖的神经体液控制至关重要。在患有GnRH缺乏症 (即特发性促性腺激素性性腺功能减退症) 的患者中使用了遗传工具,这是一种由脉动GnRH正常模式失败引起的临床综合征,以发现GnRH分泌的上游调节剂 (1)。2003年,两个近亲谱系的纯合作图导致两组 (2,3) 鉴定了KISS1R (一种g蛋白偶联受体) 功能突变的丧失。同时,Kiss1r(-/-) 小鼠被证明是人类GnRH缺陷状态的现象,表明KISS1R/Kiss1r的功能在整个哺乳动物物种中是保守的 (4)。就在这些人类遗传发现之前,kisspeptin-1受体的配体 [KISS1R; 也称为g蛋白偶联受体54 (GPR54)] 被发现是kisspeptin。此后不久,大量的实验研究开始收集遗传,表达,生理,转基因,敲低和电生理学数据,以表征kisspeptin的生理学及其在调节GnRH释放中的重要作用。

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