Naor Z, Harris D, Shacham S
Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.
Front Neuroendocrinol. 1998 Jan;19(1):1-19. doi: 10.1006/frne.1997.0162.
Gonadotropin-releasing hormone (GnRH), the first key hormone of reproduction, is synthesized in the hypothalamus and is released in a pulsatile manner to stimulate pituitary gonadotrope-luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and release. Gonadotropes represent only about 10% of pituitary cells and are divided into monohormonal cells (18% LH and 22% FSH cells) and 60% multihormonal (LH + FSH) cells. GnRH binds to a specific seven transmembrane domain receptor which is coupled to Gq and activates sequentially different phospholipases to provide Ca2+ and lipid-derived messenger molecules. Initially, phospholipase C is activated, followed by activation of both phospholipase A2 (PLA2) and phospholipase D (PLD). Generation of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol (DAG) lead to mobilization of intracellular pools of Ca2+ and activation of protein kinase C (PKC). Early DAG and Ca2+, derived via enhanced phosphoinositide turnover, might be involved in rapid activation of selective Ca(2+)-dependent, conventional PKC isoforms (cPKC). On the other hand, late DAG, derived from phosphatidic acid (PA) via PLD, may activate Ca(2+)-independent novel PKC isoforms (nPKC). In addition, arachidonic acid (AA) which is liberated by activated PLA2, might also support selective activation of PKC isoforms (PKCs) with or without other cofactors. Differential cross-talk of Ca2+, AA, and selective PKCs might generate a compartmentalized signal transduction cascade to downstream elements which are activated during the neurohormone action. Among those elements is the mitogen-activated protein kinase (MAPK) cascade which is activated by GnRH in a PKC-, Ca(2+)-, and protein tyrosine kinase (PTK)-dependent fashion. Transcriptional regulation can be mediated by the activation of transcription factors such as c-fos by MAPK. Indeed, GnRH activates the expression of both c-jun and c-fos which might participate in gene regulation via the formation of AP-1. The signaling cascade leading to gonadotropin (LH and FSH) gene regulation by GnRH is still not known and might involve the above-mentioned cascades. AA and selective lipoxygenase products such as leukotriene C4 also participate in GnRH action, possibly by cross-talk with PKCs, or by an autocrine/paracrine amplification cycle. A complex combinatorial, spatial and temporal cross-talk of the above messenger molecules seems to mediate the diverse effects elicited by GnRH, the first key hormone of the reproductive cycle.
促性腺激素释放激素（GnRH）是生殖过程中的首个关键激素，在下丘脑中合成，并以脉冲方式释放，以刺激垂体促性腺激素细胞合成和释放促黄体生成素（LH）和促卵泡激素（FSH）。促性腺激素细胞仅占垂体细胞的约10%，分为单激素细胞（18%的LH细胞和22%的FSH细胞）和60%的多激素（LH + FSH）细胞。GnRH与一种特定的七跨膜结构域受体结合，该受体与Gq偶联，并依次激活不同的磷脂酶，以提供Ca2+和脂质衍生的信使分子。最初，磷脂酶C被激活，随后磷脂酶A2（PLA2）和磷脂酶D（PLD）也被激活。第二信使肌醇1,4,5-三磷酸和二酰基甘油（DAG）的生成导致细胞内Ca2+库的动员和蛋白激酶C（PKC）的激活。通过增强磷脂酰肌醇周转产生的早期DAG和Ca2+可能参与选择性Ca(2+)依赖性常规PKC亚型（cPKC）的快速激活。另一方面，通过PLD从磷脂酸（PA）衍生而来的晚期DAG可能激活Ca(2+)非依赖性新型PKC亚型（nPKC）。此外，由激活的PLA2释放的花生四烯酸（AA）也可能支持PKC亚型（PKCs）在有或没有其他辅助因子的情况下的选择性激活。Ca2+、AA和选择性PKCs之间的差异相互作用可能产生一个分隔的信号转导级联，传递给在神经激素作用期间被激活的下游元件。这些元件包括丝裂原活化蛋白激酶（MAPK）级联，它由GnRH以PKC、Ca(2+)和蛋白酪氨酸激酶（PTK）依赖性方式激活。转录调节可由MAPK等转录因子的激活介导，如c-fos。事实上，GnRH激活c-jun和c-fos的表达，它们可能通过形成AP-1参与基因调控。导致GnRH对促性腺激素（LH和FSH）基因调控的信号级联仍不清楚，可能涉及上述级联。AA和选择性脂氧合酶产物如白三烯C4也参与GnRH作用，可能是通过与PKCs相互作用，或通过自分泌/旁分泌放大循环。上述信使分子复杂的组合、空间和时间相互作用似乎介导了GnRH（生殖周期的首个关键激素）引发的多种效应。
