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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
neuroscience
Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation
Journal of Neuroscience, Volume 29, No. 12, Year 2009
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Description
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. Copyright © 2009 Society for Neuroscience.
Authors & Co-Authors
Roseweir, Antonia Kathryn
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
Kauffman, Alexander S.
United States, Seattle
University of Washington School of Medicine
Smith, Jeremy T.
Australia, Clayton
Monash University
Guerriero, Kathryn A.
United States, Madison
Wisconsin National Primate Research Center
Morgan, Kevin
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
Pielecka-Fortuna, Justyna
United States, Charlottesville
University of Virginia
Pineda, Rafael
Spain, Cordoba
Universidad de Córdoba
Gottsch, Michelle L.
United States, Seattle
University of Washington School of Medicine
Tena-Sempere, Manuel
Spain, Cordoba
Universidad de Córdoba
Moenter, Suzanne M.
United States, Charlottesville
University of Virginia
Terasawa, Ei
United States, Madison
Wisconsin National Primate Research Center
Clarke, Iain J.
Australia, Clayton
Monash University
Steiner, Robert A.
United States, Seattle
University of Washington School of Medicine
Millar, Robert P.
United Kingdom, Edinburgh
University of Edinburgh, College of Medicine and Veterinary Medicine
South Africa, Cape Town
University of Cape Town
Statistics
Citations: 14
Authors: 14
Affiliations: 7
Identifiers
Doi:
10.1523/JNEUROSCI.5740-08.2009
ISSN:
02706474
e-ISSN:
15292401
Research Areas
Cancer
Participants Gender
Female