Differential regulation of gonadotropin-releasing hormone by corticotropin-releasing factor family peptides in hypothalamic N39 cells

► There is a close interaction between the HPG axis and the HPA axis. ► CRF and Ucn2 can modulate GnRH mRNA and protein levels via each specific CRF receptor subtype in N39 cells. ► Differential regulation of GnRH by CRF family peptides contributes to the stress response and homeostasis in the GnRH cells. Corticotropin-releasing factor (CRF) is involved in a variety of physiological functions including regulation of hypothalamo–pituitary–adrenal axis activity during stressful periods. Urocortins (Ucns) are known to be members of the CRF family peptides. CRF has a high affinity for CRF receptor type 1 (CRF1 receptor). Both Ucn2 and Ucn3 have very high affinity for CRF receptor type 2 (CRF2 receptor) with little or no binding affinity for the CRF1 receptor. Gonadotropin-releasing hormone (GnRH) is known to be involved in the regulation of the stress response. Gonadotropin-inhibitory hormone (GnIH) neurons interact directly with GnRH neurons, and the action of GnIH is mediated by a novel G-protein coupled receptor, Gpr147. This study aimed to explore the possible function of CRF family peptides and the regulation of GnRH mRNA in hypothalamic GnRH cells. Both mRNA and protein expression of the CRF1 receptor and CRF2 receptor were found in hypothalamic GnRH N39 cells. CRF suppressed GnRH mRNA levels via the CRF1 receptor, while Ucn2 increased the levels via the CRF2 receptor. Both CRF and Ucn2 increased Gpr147 mRNA levels. The results indicate that CRF and Ucn2 can modulate GnRH mRNA levels via each specific CRF receptor subtype. Finally, CRF suppressed GnRH protein levels, while Ucn2 increased the levels. Differential regulation of GnRH by CRF family peptides may contribute to the stress response and homeostasis in GnRH cells.