Cyclic GMP Signaling Pathways in the Ovary

生殖能力受作用于卵巢的多种因素影响。垂体激素卵泡刺激素(FSH)诱导颗粒细胞功能成熟，与增加雌二醇(E_2)合成、抑制素产生和黄体生成素受体表达有关。FSH对颗粒细胞成熟的作用是通过膜结合的受体介导的，该受体的占据导致腺酰环化酶的激活，随后产生cAMP并激活cAMP依赖的信号通路。除了FSH的作用外，颗粒细胞的成熟还受到其他激素和因素的调节，这些激素和因素通过不同的信号转导途径发挥作用。我们最近证实了一氧化氮(NO)及其相关的第二信使cGMP对血管内皮细胞的抑制作用。 促性腺激素诱导的雌二醇合成、抑制素产生和黄体生成素受体的表达。有趣的是，NO和cGMP对颗粒细胞成熟的抑制作用与抑制FSH诱导的cAMP积累有关。虽然从这些和其他研究中可以清楚地看到，cGMP可能是颗粒细胞功能的有效调节者，但cGMP抑制FSH诱导的细胞成熟和cAMP水平的机制仍不清楚。一般说来，cGMP通过调节磷酸二酯酶(PDE)活性、激活依赖于cGMP的蛋白激酶G(PKG)和调节环核苷酸门控通道(CNGs)来作用于靶细胞。我们已经证实cGMP和NO对颗粒细胞成熟和cAMP积累的抑制作用不是通过PDES活性增加来实现的，这表明cGMP对cAMP产生的影响以及cGMP作用的其他介质的参与。令人惊讶的是，关于腺酰环化酶亚型、PKG和CNGs在卵巢中的表达和作用，人们知之甚少。因此，拟议的研究将审查cGMP的影响 对颗粒细胞成熟的影响反映了与腺苷环化酶、蛋白酪氨酸氨基转移酶和神经生长因子的相互作用。此外，这些研究还将检测腺酰环化酶异构体、PKG和CNGs在大鼠颗粒细胞中的调节表达。这些研究的结果将提供关于cGMP、腺苷环化酶、PKG和CNGs在卵巢功能中作用的重要新信息，并可能导致与避孕和不孕症治疗相关的新的临床方法。

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.