Human type II GnRH receptor mediates effects of GnRH on cell proliferation.
GnRH (gonadotropin-releasing hormone) is well-known as the central regulator of the reproductive system through its stimulation of gonadotropin release from the pituitary. Progress in studies on GnRH demonstrated that GnRH has both inhibitory and stimulatory effects on cell proliferation depending on the cell type, and the mechanisms of these effects have been intensively studied. However, even human GnRH receptors which mediate GnRH stimulation have not been completely identified. In the present study, we showed that the inhibitory and stimulatory effects of GnRH on colony-formation using four cell lines and have demonstrated that the inhibitory and stimulatory effects of GnRH exhibit distinctly different patterns of ligand sensitivity. This result strongly suggests that the two opposite effects of GnRH occur via different types of GnRH receptors, however expressional analyses of human GnRH receptors did not exhibit the significantly different pattern between negatively and positively responding cell lines. Then, in order to identify the GnRH receptors involved in the two opposite effects, effects of GnRH were analysed under the conditions that human GnRH receptors were knocked down by the technique of RNA interference. Consequently, it was found that human type II GnRH receptor mediates GnRH stimulation and its splice variant determines the direction of the response to GnRH. These results are the first clear evidence for the functionality of human type II GnRH receptor. Therefore our novel findings are quite noticeable and will greatly contribute to the studies on the mechanisms of the effects of GnRH on cell proliferation in the future.
Enomoto
Masahiro
M
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.
Endo
Daisuke
D
Kawashima
Seiichiro
S
Park
Min Kyun
MK
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D017931:DNA Primers; C427484:GNRHR2 protein, human; D008024:Ligands; D034741:RNA, Small Interfering; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone