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-NH(2) 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'-(gamma-[(35)S]thio)-triphosphate (GTP-gamma-[(35)S]) binding with EC(50) values of 13+/-4 and 16+/-4 nM, respectively. hKisspeptin-13 induced the binding with an EC(50) value of 110+/-50 nM, whereas mKisspeptin-13 induced very modestly activation with an EC(50) value>2 microM. 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.
Lyubimov
Y
Y
Institute of Biomedicine/Anatomy and Neuroscience Center, University of Helsinki, Helsinki, Finland.
Engstrom
M
M
Wurster
S
S
Savola
J-M
JM
Korpi
E R
ER
Panula
P
P
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D059648:Kisspeptins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009434:Neural Pathways / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000378:metabolism*; D012098:Reproduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D014982:Xenopus laevis
C106628:KISS1 protein, human; D059648:Kisspeptins; D018013:Receptors, Neuropeptide; D025521:Tumor Suppressor Proteins; C083929:neuropeptide FF receptor