Intracellular Signaling Pathways Mediated by the Gonadotropin-releasing Hormone (GnRH) Receptor

The hypothalamic gonadotropin-releasing hormone (GnRH) is a key regulator of the reproductive system, triggering the synthesis and release of LH and FSH in the pituitary. GnRH transmits its signal via two specific serpentine receptors that belong to the large group of G-protein coupled receptors (GPCRs). Here we review the intracellular signaling pathways mediated by the GnRH receptor (GnRHR). In pituitary-derived alpha T3-1 cells, a widely used model for GnRH action, GnRHR signaling includes activation of mitogen-activated protein kinase (MAPK) cascades, which provide an important link for the transmission of signals from the cell surface to the nucleus and play a role in the regulation of gonadotropin transcription. Activation of ERK--one of the MAPK cascades--by GnRH in these cells depends mainly on the phosphorylation of Raf1 by PKC, supported by a pathway involving c-Src, dynamin, and Ras. On the other hand, the activation of JNK, another MAPK cascade, involves PKC, c-Src, CDC42/Rac1, and probably MEKK1. The GnRHR is also expressed in non-pituitary cells and was found to be involved in the inhibition of cell proliferation in certain cells. Therefore, GnRHR represents a potential target for GnRH-analogs used for cancer treatment. Interestingly, the signaling mechanism of the GnRHR in other cell types significantly differs from that in pituitary cells. Studies conducted in GnRHR-expressing COS7 cells have shown that GnRHR transmits its signals mainly via Gi, EGF receptor, c-Src, and is not dependent on PKC. Understanding the signaling mechanisms elicited by GnRHR can shed light on the mechanism of action of GnRH in pituitary and extra-pituitary tissues.