Human kisspeptins activate neuropeptide FF2 receptor

We studied the possible activation of a neuropeptide FF2 receptor (NPFF2R) by kisspeptins, neuropeptides derived from the mouse and human metastin or Kiss-1 precursor. The hypothesis was that the human kisspeptins, which share the C-terminal dipeptide RF-NH2 with NPFF, might activate the NPFF2R, as has previously been shown for two related peptides, prolactin-releasing peptide and RF-amide-related peptide. Using two-electrode voltage clamp of Xenopus oocytes, we found that 100 nM NPFF strongly activated the human NPFF2R expressed together with rat GIRK1/4 inward rectifier potassium channels, and that 100 nM hKisspeptin-13 and hKisspeptin-8 had about 25% relative efficacy to that of NPFF. The current response induced by hKisspeptin-13 was proportional to its concentration (1-500 nM). The corresponding mouse peptides resulted in low activation only. When hNPFF2R was expressed in Chinese hamster ovary (CHO) cells, NPFF and its stable analog (1DMe)Y8Fa induced guanosine 5′-(γ-[35S]thio)-triphosphate (GTP-γ-[35S]) binding with EC50 values of 13±4 and 16±4 nM, respectively. hKisspeptin-13 induced the binding with an EC50 value of 110±50 nM, whereas mKisspeptin-13 induced very modestly activation with an EC50 value>2 μM. The results suggest that, besides regulation of reproduction, kisspeptins have a potential to mediate physiological effects on, for example autonomic regulation and nociception in man via the NPFF2R pathways.