The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone.
The Kiss1 gene codes for kisspeptin, which binds to GPR54, a G-protein-coupled receptor. Kisspeptin and GPR54 are expressed in discrete regions of the forebrain, and they have been implicated in the neuroendocrine regulation of reproduction. Kiss1-expressing neurons are thought to regulate the secretion of gonadotropin-releasing hormone (GnRH) and thus coordinate the estrous cycle in rodents; however, the precise role of kisspeptin-GPR54 signaling in the regulation of gonadotropin secretion is unknown. In this study, we used female mice with deletions in the GPR54 gene [GPR54 knock-outs (KOs)] to test the hypothesis that kisspeptin-GPR54 signaling provides the drive necessary for tonic GnRH/luteinizing hormone (LH) release. We predicted that tonic GnRH/LH secretion would be disrupted in GPR54 KOs and that such animals would be incapable of showing a compensatory rise in LH secretion after ovariectomy. As predicted, we found that GPR54 KO mice do not exhibit a postovariectomy rise in LH, suggesting that tonic GnRH secretion is disrupted in the absence of kisspeptin-GPR54 signaling. We also postulated that kisspeptin-GPR54 signaling is critical for the generation of the estradiol (E)-induced GnRH/LH surge and thus E should be incapable of inducing an LH surge in the absence of GPR54. However, we found that E induced Fos expression in GnRH neurons and produced a GnRH-dependent LH surge in GPR54 KOs. Thus, in mice, kisspeptin-GPR54 signaling is required for the tonic stimulation of GnRH/LH secretion but is not required for generating the E-induced GnRH/LH surge.
Dungan
Heather M
HM
Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195, USA.
Gottsch
Michelle L
ML
Zeng
Hongkui
H
Gragerov
Alexander
A
Bergmann
John E
JE
Vassilatis
Demetrios K
DK
Clifton
Donald K
DK
Steiner
Robert A
RA
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D059648:Kisspeptins; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy / Q000379:methods; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011863:Radioimmunoassay / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000502:physiology*; D000074502:Receptors, Kisspeptin-1; D015398:Signal Transduction / Q000502:physiology*
D004791:Enzyme Inhibitors; C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D009842:Oligopeptides; D016761:Oncogene Proteins v-fos; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; C109238:acyline