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.
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