Krsmanovic L Z, Martinez-Fuentes A J, Arora K K, Mores N, Navarro C E, Chen H C, Stojilkovic S S, Catt K J
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Endocrinology. 1999 Mar;140(3):1423-31. doi: 10.1210/endo.140.3.6588.
Episodic hormone secretion is a characteristic feature of the hypothalamo-pituitary-gonadal system, in which the profile of gonadotropin release from pituitary gonadotrophs reflects the pulsatile secretory activity of GnRH-producing neurons in the hypothalamus. Pulsatile release of GnRH is also evident in vitro during perifusion of immortalized GnRH neurons (GT1-7 cells) and cultured fetal hypothalamic cells, which continue to produce bioactive GnRH for up to 2 months. Such cultures, as well as hypothalamic tissue from adult rats, express GnRH receptors as evidenced by the presence of high-affinity GnRH binding sites and GnRH receptor transcripts. Furthermore, individual GnRH neurons coexpress GnRH and GnRH receptors as revealed by double immunostaining of hypothalamic cultures. In static cultures of hypothalamic neurons and GT1-7 cells, treatment with the GnRH receptor antagonist, [D-pGlu1, D-Phe2, D-Trp(3,6)]GnRH caused a prominent increase in GnRH release. In perifused hypothalamic cells and GT1-7 cells, treatment with the GnRH receptor agonist, des-Gly10-[D-Ala6]GnRH N-ethylamide, reduced the frequency and increased the amplitude of pulsatile GnRH release, as previously observed in GT1-7 cells. In contrast, exposure to the GnRH antagonist analogs abolished pulsatile secretion and caused a sustained and progressive increase in GnRH release. These findings have demonstrated that GnRH receptors are expressed in hypothalamic GnRH neurons, and that receptor activation is required for pulsatile GnRH release in vitro. The effects of GnRH agonist and antagonist analogs on neuropeptide release are consistent with the operation of an ultrashort-loop autocrine feedback mechanism that exerts both positive and negative actions that are necessary for the integrated control of GnRH secretion from the hypothalamus.
间歇性激素分泌是下丘脑 - 垂体 - 性腺系统的一个特征，其中垂体促性腺细胞释放促性腺激素的模式反映了下丘脑产生促性腺激素释放激素（GnRH）的神经元的脉冲式分泌活动。在永生化GnRH神经元（GT1 - 7细胞）和培养的胎儿下丘脑细胞的灌流过程中，GnRH的脉冲式释放在体外也很明显，这些细胞可持续产生生物活性GnRH长达2个月。这种培养物以及成年大鼠的下丘脑组织表达GnRH受体，高亲和力GnRH结合位点和GnRH受体转录本的存在证明了这一点。此外，下丘脑培养物的双重免疫染色显示，单个GnRH神经元共表达GnRH和GnRH受体。在下丘脑神经元和GT1 - 7细胞的静态培养中，用GnRH受体拮抗剂[D - pGlu1，D - Phe2，D - Trp(3,6)]GnRH处理导致GnRH释放显著增加。在灌流的下丘脑细胞和GT1 - 7细胞中，用GnRH受体激动剂去甘氨酰胺 - [D - 丙氨酸6]GnRH N - 乙基酰胺处理，降低了脉冲式GnRH释放的频率并增加了其幅度，这与之前在GT1 - 7细胞中观察到的情况一致。相反，暴露于GnRH拮抗剂类似物会消除脉冲式分泌，并导致GnRH释放持续且逐渐增加。这些发现表明，GnRH受体在下丘脑GnRH神经元中表达，并且受体激活对于体外脉冲式GnRH释放是必需的。GnRH激动剂和拮抗剂类似物对神经肽释放的影响与超短环自分泌反馈机制的运作一致，该机制发挥着正负两种作用，这对于下丘脑GnRH分泌的综合控制是必要的。
