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The Journal of Neuroscience, October 31, 2007, 27(44):12088-12095; doi:10.1523/JNEUROSCI.2748-07.2007

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Behavioral/Systems/Cognitive
The Role of Kisspeptin–GPR54 Signaling in the Tonic Regulation and Surge Release of Gonadotropin-Releasing Hormone/Luteinizing Hormone

Heather M. Dungan,¹ Michelle L. Gottsch,² Hongkui Zeng,³ Alexander Gragerov,⁴ John E. Bergmann,⁴ Demetrios K. Vassilatis,⁵ Donald K. Clifton,² and Robert A. Steiner^1,2

Departments of ¹Physiology and Biophysics and ²Obstetrics and Gynecology, University of Washington, Seattle, Washington 98195, ³Allen Brain Institute, Seattle, Washington 98101, ⁴Omeros Corporation, Seattle, Washington 98101, and ⁵Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece

Correspondence should be addressed to Dr. Robert A. Steiner, Department of Obstetrics and Gynecology, Box 356460, Health Sciences Building, 1959 Northeast Pacific Street, Seattle, WA 98195-6460. Email: steiner{at}u.washington.edu

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.

Key words: arcuate nucleus; kisspeptin; Kiss1; LH surge; AVPV; Kiss1R

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Received June 16, 2007; revised Aug. 14, 2007; accepted Sept. 13, 2007.

Correspondence should be addressed to Dr. Robert A. Steiner, Department of Obstetrics and Gynecology, Box 356460, Health Sciences Building, 1959 Northeast Pacific Street, Seattle, WA 98195-6460. Email: steiner{at}u.washington.edu

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