GNRH Signaling

The hypothalamic GnRH (Gonadotropin Releasing Hormone) plays a key role in coordinating the levels of hormones in the hypothalamic-pituitary-gonadal axis. Thus, GnRH plays a decisive role in the neuroendocrine regulation of human reproduction. GnRH acts via a specific GPCR: GnRHR and triggers the synthesis of the common α- and β-chains of the gonadotropins. GnRHR transmits its signals mainly through heterotrimeric G-proteins and is capable of activating multiple signaling pathways.The signaling events by GnRH include: activation of the G-Proteins; enhanced phosphoinositide turnover; activation of PLC ; Ca2+ mobilization and influx; translocation and activation of PKC ; and formation of bioactive lipoxygenase products that culminate in gonadotropin production and release. Binding of GnRH to GnRHR activates G-αq-, G-αi- and G-αs-dependent signaling pathways. Activation of G-αs stimulates the AC-cAMP-PKA pathway, which positively influences transcriptional activity of the GnRHR, via CREB. G-αi activation by GnRH has both positive and negative effects on the transcriptional activities of the GnRHR. G-αi counteracts the G-αs mediated CREB activation by direct inhibition of AC. G-αi also plays a positive role in the synthesis of NF-κB.The major signal transduction pathways stimulated by GnRH are initiated by activation of G-αq that contributes to the activation of PLC-β. The consequent PIP2 activation, Ca2+ mobilization, production of DAG and activation of PKCs, switch on the MAPK cascade. The IP3-released calcium is one of the critical signals required for secretion of the gonadotropic hormones: LH and FSH. This secretory function is accomplished by the activation of CamKII by calcium leading to the activation of CREB. Activation of ERKs by GnRH depends mainly on the phosphorylation of Raf by PKC. The main pathway involves a direct activation of Raf by PKC, and this step is partially dependent on a second pathway consisting of Ras activation, which occurs in a dynamin-dependent manner, downstream of Src. Apart from activating the ERK cascade, GnRH also stimulates the activity of other stress-related MAPK cascades (JNK, BMK1, and p38). The mechanism of BMK1 and p38 activation by GnRH is PKC-dependent. The EGFR is transactivated by the GnRH-induced Src kinase. The activated EGFR provides docking sites for several signaling proteins, including SOS and GRB2, which leads to activation of the Ras-Raf-MEK-ERK pathway. Activation of BMK1, JNK and ERK provide a route for activation of the transcription factors: c-fos and c-jun that form a dimer which activates the AP1 responsive element present in both LH and FSH promoters. Other trans factors like Elk1 , ATF2, CREB and NFκB are also involved in increased transcription of LH and FSH.In addition to the synthesis of the gonadotropins, cell motility and migration also gets affected by the GnRH signaling. The GnRH-activated Src Kinases bring about phosphorylation of the focal adhesion tyrosine kinase, FAK, which is then recruited to the plasma membrane focal adhesion complex. These protein signaling complexes assemble on integrin heterodimers following integrin engagement of ECM proteins. Integrin signaling, via FAK can activate CDC42 and Rac1 resulting in cytoskeletal rearrangement and membrane extension. Activated Rac1 can in turn stimulate ERK which again leads to cell motility and migration.The expression of GnRH and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary and endometrium. GnRH and GnRH analogues have extensive application in the treatment of human diseases.