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The Journal of Neuroscience, March 25, 2009, 29(12):3920-3929; doi:10.1523/JNEUROSCI.5740-08.2009

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Cellular/Molecular
Discovery of Potent Kisspeptin Antagonists Delineate Physiological Mechanisms of Gonadotropin Regulation

Antonia K. Roseweir,¹ Alexander S. Kauffman,² Jeremy T. Smith,³ Kathryn A. Guerriero,⁴ Kevin Morgan,¹ Justyna Pielecka-Fortuna,⁵ Rafael Pineda,⁶ Michelle L. Gottsch,² Manuel Tena-Sempere,⁶ Suzanne M. Moenter,⁵ Ei Terasawa,⁴ Iain J. Clarke,³ Robert A. Steiner,² and Robert P. Millar^1,7

¹Medical Research Council Human Reproductive Sciences Unit, The Queens Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom, ²Department of Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington 98195, ³Department of Physiology, Monash University, Victoria 3800, Australia, ⁴Wisconsin National Primate Centre and Department of Pediatrics, University of Wisconsin–Madison, Madison, Wisconsin 53715, ⁵Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908, ⁶Physiology Section, University of Cordoba, 14004 Cordoba, Spain, and ⁷Department of Medical Biochemistry, University of Cape Town, 7925 Cape Town, South Africa

Correspondence should be addressed to Robert P. Millar, Medical Research Council Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Email: r.millar{at}hrsu.mrc.ac.uk

Neurons that produce gonadotropin-releasing hormone (GnRH) are the final common pathway by which the brain regulates reproduction. GnRH neurons are regulated by an afferent network of kisspeptin-producing neurons. Kisspeptin binds to its cognate receptor on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion, thus gating down-stream events supporting reproduction. We have developed kisspeptin antagonists to facilitate the direct determination of the role of kisspeptin neurons in the neuroendocrine regulation of reproduction. In vitro and in vivo studies of analogues of kisspeptin-10 with amino substitutions have identified several potent and specific antagonists. A selected antagonist was shown to inhibit the firing of GnRH neurons in the brain of the mouse and to reduce pulsatile GnRH secretion in female pubertal monkeys; the later supporting a key role of kisspeptin in puberty onset. This analog also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the postcastration rise in LH in sheep, rats, and mice, suggesting that kisspeptin neurons mediate the negative feedback effect of sex steroids on gonadotropin secretion in mammals. The development of kisspeptin antagonists provides a valuable tool for investigating the physiological and pathophysiological roles of kisspeptin in the regulation of reproduction and could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer.

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Received Dec. 1, 2008; revised Jan. 22, 2009; accepted Feb. 6, 2009.

Correspondence should be addressed to Robert P. Millar, Medical Research Council Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Email: r.millar{at}hrsu.mrc.ac.uk

This article has been cited by other articles:

				C. N. Jayasena, G. M. K. Nijher, O. B. Chaudhri, K. G. Murphy, A. Ranger, A. Lim, D. Patel, A. Mehta, C. Todd, R. Ramachandran, et al. Subcutaneous Injection of Kisspeptin-54 Acutely Stimulates Gonadotropin Secretion in Women with Hypothalamic Amenorrhea, But Chronic Administration Causes Tachyphylaxis J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4315 - 4323. [Abstract] [Full Text] [PDF]

				A. E. Oakley, D. K. Clifton, and R. A. Steiner Kisspeptin Signaling in the Brain Endocr. Rev., October 1, 2009; 30(6): 713 - 743. [Abstract] [Full Text] [PDF]

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