https://www.selleckchem.com/products/lificiguat-yc-1.html Gonadotropin-releasing hormone (GnRH) is the master regulator of the hypothalamic-pituitary-gonadal (HPG) axis, and therefore of fertility and reproduction. The release pattern of GnRH by the hypothalamus includes both pulses and surges. However, despite a considerable body of evidence in support of a determinant role for kisspeptin, the mechanisms regulating a GnRH pulse and surge remain a topic of debate. In this review we challenge the view of kisspeptin as an absolute "monarch", and instead present the idea of a Kisspeptin-nNOS-GnRH or "KiNG" network that is responsible for generating the "GnRH pulse" and "GnRH surge". In particular, the neuromodulator nitric oxide (NO) has opposite effects to kisspeptin on GnRH secretion in many respects, acting as the Yin to kisspeptin's Yang and creating a dynamic system in which kisspeptin provides the "ON" signal, promoting GnRH release, while NO mediates the "OFF" signal, acting as a tonic brake on GnRH secretion. This interplay between an activator and an inhibitor, which is in turn fine-tuned by the gonadal steroid environment, thus leads to the generation of GnRH pulses and surges and is crucial for the proper development and function of the reproductive axis.Growth factors regulate ovarian follicle development and they signal through intracellular pathways including mitogen-activated protein kinase (MAPK) phosphorylation, which is negatively regulated by a subfamily of 23 dual-specificity phosphatases (DUSP). Using sheep granulosa cells as a model, we detected mRNA encoding 16 DUSPs in vivo and in vitro. Stimulation of cells in vitro with FGF2 increased (p less then 0.05) abundance of DUSP1, DUSP2, DUSP5 and DUSP6 mRNA, and abundance of DUSP1 and DUSP6 proteins (p less then 0.05). In contrast, neither FGF8b nor FGF18 had any major effect on DUSP mRNA abundance. Inhibition of DUSP6 action with the inhibitor BCI significantly increased (p less then 0.05) MAPK8 (JN