Cyclic GMP Signaling Pathways in the Ovary

生殖能力受到许多作用于卵巢的因素的影响。垂体激素促卵泡激素（FSH）诱导颗粒细胞的功能成熟，与雌二醇（E2）合成增加、卵泡刺激素产生和LH受体表达相关。FSH对颗粒细胞成熟的作用由膜结合受体介导，其占据导致腺苷酸环化酶激活，随后产生cAMP并激活cAMP依赖性信号通路。除了FSH的作用外，颗粒细胞成熟还受到其他激素和因子的调节，这些激素和因子通过不同的信号转导途径起作用。我们最近已经证明了一氧化氮（NO）及其相关的第二信使cGMP的抑制作用， FSH诱导的E2合成、E2受体产生和LH受体表达。有趣的是，NO和cGMP对颗粒细胞成熟的抑制作用与FSH诱导的cAMP积累减弱有关。虽然从这些和其他研究中可以清楚地看出cGMP可能作为颗粒细胞功能的有效调节剂，但cGMP抑制FSH诱导的细胞成熟和cAMP水平的机制仍然未知。一般而言，已知cGMP通过调节磷酸二酯酶（PDE）活性、激活cGMP依赖性蛋白激酶G（PKG）和调节环核苷酸门控通道（CNG）作用于靶细胞。我们已经建立了cGMP和NO对颗粒细胞成熟和cAMP积累的抑制作用不是由PDE活性增加介导的，表明对cAMP产生的影响和cGMP作用的其他介质的参与。令人惊讶的是，很少有人知道的表达和行动的腺苷酸环化酶亚型，PKG和CNG在卵巢。因此，拟议的研究将检查cGMP的影响是否 对颗粒细胞成熟的影响反映了与腺苷酸环化酶、PKG和CNG的相互作用。此外，这些研究将检查大鼠颗粒细胞中腺苷酸环化酶亚型，PKG和CNG的表达调控。这些研究的结果将提供关于cGMP、腺苷酸环化酶、PKG和CNG在卵巢功能中的作用的重要新信息，并可能导致与避孕和不孕症治疗相关的新临床方法。

Reproductive competence is influenced by many factors acting on the ovary. The pituitary hormone follicle-stimulating hormone (FSH) induces functional maturation of granulosa cells, associated with increased estradiol (E2) synthesis, inhibin production, and LH receptor expression. The actions of FSH on granulosa cell maturation are mediated by a membrane-bound receptor whose occupancy results in activation of adenylyl cyclase, with subsequent production of cAMP and activation of cAMP-dependent signaling pathways. In addition to the effects of FSH, granulosa cell maturation is also modulated by other hormones and factors, which act through different signal transduction pathways. We have recently demonstrated inhibitory influences of nitric oxide (NO) and its associated second messenger, cGMP, on FSH-induced E2 synthesis, inhibin production, and LH receptor expression. Interestingly, the inhibitory effects of NO and cGMP on granulosa cell maturation are associated with attenuated FSH-induced cAMP accumulation. While it is clear from these and other studies that cGMP may act as a potent regulator of granulosa cell function, the mechanisms by which cGMP inhibit FSH-induced cell maturation and cAMP levels remain unknown. In general, cGMP is known to act on target cells by regulation of phosphodiesterase (PDE) activity, by activation of cGMP-dependent protein kinase G (PKG), and by regulation of cyclic nucleotide-gated channels (CNGs). We have established that the inhibitory effects of cGMP and NO on granulosa cell maturation and cAMP accumulation are not mediated by increased activity of PDEs, indicating influences on cAMP production and involvement of other mediators of cGMP action. Surprisingly, little is known regarding the expression and actions of adenylyl cyclase isoforms, PKG, and CNGs in the ovary. Therefore, the proposed studies will examine whether the effects of cGMP on granulosa cell maturation reflect interactions with adenylyl cyclase, PKG, and CNGs. Furthermore, these studies will examine the regulated expression of adenylyl cyclase isoforms, PKG, and CNGs in rat granulosa cells. Findings from these studies will provide important new information regarding the roles of cGMP, adenylyl cyclase, PKG, and CNGs in ovarian functions, and may lead to new clinical approaches related to contraception and infertility treatment.