TY - JOUR T1 - Discovery of Potent Kisspeptin Antagonists Delineate Physiological Mechanisms of Gonadotropin Regulation JF - The Journal of Neuroscience JO - J. Neurosci. SP - 3920 LP - 3929 DO - 10.1523/JNEUROSCI.5740-08.2009 VL - 29 IS - 12 AU - Antonia K. Roseweir AU - Alexander S. Kauffman AU - Jeremy T. Smith AU - Kathryn A. Guerriero AU - Kevin Morgan AU - Justyna Pielecka-Fortuna AU - Rafael Pineda AU - Michelle L. Gottsch AU - Manuel Tena-Sempere AU - Suzanne M. Moenter AU - Ei Terasawa AU - Iain J. Clarke AU - Robert A. Steiner AU - Robert P. Millar Y1 - 2009/03/25 UR - http://www.jneurosci.org/content/29/12/3920.abstract N2 - 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. ER -