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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation</title><author><name sortKey="Roseweir, Antonia K" sort="Roseweir, Antonia K" uniqKey="Roseweir A" first="Antonia K." last="Roseweir">Antonia K. Roseweir</name><affiliation><nlm:aff id="A1">MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.</nlm:aff></affiliation></author><author><name sortKey="Kauffman, Alexander S" sort="Kauffman, Alexander S" uniqKey="Kauffman A" first="Alexander S." last="Kauffman">Alexander S. Kauffman</name><affiliation><nlm:aff id="A2">Department of Obstetrics and Gynecology, School of Medicine, Box 356460, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Smith, Jeremy T" sort="Smith, Jeremy T" uniqKey="Smith J" first="Jeremy T." last="Smith">Jeremy T. Smith</name><affiliation><nlm:aff id="A3">Department of Physiology, PO Box 13F, Monash University, Victoria 3800, Australia.</nlm:aff></affiliation></author><author><name sortKey="Guerriero, Kathryn A" sort="Guerriero, Kathryn A" uniqKey="Guerriero K" first="Kathryn A." last="Guerriero">Kathryn A. Guerriero</name><affiliation><nlm:aff id="A4">Wisconsin National Primate Centre & Department of Pediatrics, University of Wisconsin-Madison, WI 53715, USA</nlm:aff></affiliation></author><author><name sortKey="Morgan, Kevin" sort="Morgan, Kevin" uniqKey="Morgan K" first="Kevin" last="Morgan">Kevin Morgan</name><affiliation><nlm:aff id="A1">MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.</nlm:aff></affiliation></author><author><name sortKey="Pielecka Fortuna, Justyna" sort="Pielecka Fortuna, Justyna" uniqKey="Pielecka Fortuna J" first="Justyna" last="Pielecka-Fortuna">Justyna Pielecka-Fortuna</name><affiliation><nlm:aff id="A5">Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, VA</nlm:aff></affiliation></author><author><name sortKey="Pineda, Rafael" sort="Pineda, Rafael" uniqKey="Pineda R" first="Rafael" last="Pineda">Rafael Pineda</name><affiliation><nlm:aff id="A6">Physiology Section, University of Cordoba, 14004 Cordoba, Spain</nlm:aff></affiliation></author><author><name sortKey="Gottsch, Michelle L" sort="Gottsch, Michelle L" uniqKey="Gottsch M" first="Michelle L." last="Gottsch">Michelle L. Gottsch</name><affiliation><nlm:aff id="A2">Department of Obstetrics and Gynecology, School of Medicine, Box 356460, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Tena Sempere, Manuel" sort="Tena Sempere, Manuel" uniqKey="Tena Sempere M" first="Manuel" last="Tena-Sempere">Manuel Tena-Sempere</name><affiliation><nlm:aff id="A6">Physiology Section, University of Cordoba, 14004 Cordoba, Spain</nlm:aff></affiliation></author><author><name sortKey="Moenter, Suzanne M" sort="Moenter, Suzanne M" uniqKey="Moenter S" first="Suzanne M." last="Moenter">Suzanne M. Moenter</name><affiliation><nlm:aff id="A5">Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, VA</nlm:aff></affiliation></author><author><name sortKey="Terasawa, Ei" sort="Terasawa, Ei" uniqKey="Terasawa E" first="Ei" last="Terasawa">Ei Terasawa</name><affiliation><nlm:aff id="A4">Wisconsin National Primate Centre & Department of Pediatrics, University of Wisconsin-Madison, WI 53715, USA</nlm:aff></affiliation></author><author><name sortKey="Clarke, Iain J" sort="Clarke, Iain J" uniqKey="Clarke I" first="Iain J." last="Clarke">Iain J. Clarke</name><affiliation><nlm:aff id="A3">Department of Physiology, PO Box 13F, Monash University, Victoria 3800, Australia.</nlm:aff></affiliation></author><author><name sortKey="Steiner, Robert A" sort="Steiner, Robert A" uniqKey="Steiner R" first="Robert A." last="Steiner">Robert A. Steiner</name><affiliation><nlm:aff id="A2">Department of Obstetrics and Gynecology, School of Medicine, Box 356460, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Millar, Robert P" sort="Millar, Robert P" uniqKey="Millar R" first="Robert P." last="Millar">Robert P. Millar</name><affiliation><nlm:aff id="A1">MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.</nlm:aff></affiliation><affiliation><nlm:aff id="A7">Department of Medical Biochemistry, University of Cape Town, 7925, South Africa</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19321788</idno><idno type="pmc">3035813</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035813</idno><idno type="RBID">PMC:3035813</idno><idno type="doi">10.1523/JNEUROSCI.5740-08.2009</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">001461</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001461</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation</title><author><name sortKey="Roseweir, Antonia K" sort="Roseweir, Antonia K" uniqKey="Roseweir A" first="Antonia K." last="Roseweir">Antonia K. Roseweir</name><affiliation><nlm:aff id="A1">MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.</nlm:aff></affiliation></author><author><name sortKey="Kauffman, Alexander S" sort="Kauffman, Alexander S" uniqKey="Kauffman A" first="Alexander S." last="Kauffman">Alexander S. Kauffman</name><affiliation><nlm:aff id="A2">Department of Obstetrics and Gynecology, School of Medicine, Box 356460, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Smith, Jeremy T" sort="Smith, Jeremy T" uniqKey="Smith J" first="Jeremy T." last="Smith">Jeremy T. Smith</name><affiliation><nlm:aff id="A3">Department of Physiology, PO Box 13F, Monash University, Victoria 3800, Australia.</nlm:aff></affiliation></author><author><name sortKey="Guerriero, Kathryn A" sort="Guerriero, Kathryn A" uniqKey="Guerriero K" first="Kathryn A." last="Guerriero">Kathryn A. Guerriero</name><affiliation><nlm:aff id="A4">Wisconsin National Primate Centre & Department of Pediatrics, University of Wisconsin-Madison, WI 53715, USA</nlm:aff></affiliation></author><author><name sortKey="Morgan, Kevin" sort="Morgan, Kevin" uniqKey="Morgan K" first="Kevin" last="Morgan">Kevin Morgan</name><affiliation><nlm:aff id="A1">MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.</nlm:aff></affiliation></author><author><name sortKey="Pielecka Fortuna, Justyna" sort="Pielecka Fortuna, Justyna" uniqKey="Pielecka Fortuna J" first="Justyna" last="Pielecka-Fortuna">Justyna Pielecka-Fortuna</name><affiliation><nlm:aff id="A5">Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, VA</nlm:aff></affiliation></author><author><name sortKey="Pineda, Rafael" sort="Pineda, Rafael" uniqKey="Pineda R" first="Rafael" last="Pineda">Rafael Pineda</name><affiliation><nlm:aff id="A6">Physiology Section, University of Cordoba, 14004 Cordoba, Spain</nlm:aff></affiliation></author><author><name sortKey="Gottsch, Michelle L" sort="Gottsch, Michelle L" uniqKey="Gottsch M" first="Michelle L." last="Gottsch">Michelle L. Gottsch</name><affiliation><nlm:aff id="A2">Department of Obstetrics and Gynecology, School of Medicine, Box 356460, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Tena Sempere, Manuel" sort="Tena Sempere, Manuel" uniqKey="Tena Sempere M" first="Manuel" last="Tena-Sempere">Manuel Tena-Sempere</name><affiliation><nlm:aff id="A6">Physiology Section, University of Cordoba, 14004 Cordoba, Spain</nlm:aff></affiliation></author><author><name sortKey="Moenter, Suzanne M" sort="Moenter, Suzanne M" uniqKey="Moenter S" first="Suzanne M." last="Moenter">Suzanne M. Moenter</name><affiliation><nlm:aff id="A5">Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, VA</nlm:aff></affiliation></author><author><name sortKey="Terasawa, Ei" sort="Terasawa, Ei" uniqKey="Terasawa E" first="Ei" last="Terasawa">Ei Terasawa</name><affiliation><nlm:aff id="A4">Wisconsin National Primate Centre & Department of Pediatrics, University of Wisconsin-Madison, WI 53715, USA</nlm:aff></affiliation></author><author><name sortKey="Clarke, Iain J" sort="Clarke, Iain J" uniqKey="Clarke I" first="Iain J." last="Clarke">Iain J. Clarke</name><affiliation><nlm:aff id="A3">Department of Physiology, PO Box 13F, Monash University, Victoria 3800, Australia.</nlm:aff></affiliation></author><author><name sortKey="Steiner, Robert A" sort="Steiner, Robert A" uniqKey="Steiner R" first="Robert A." last="Steiner">Robert A. Steiner</name><affiliation><nlm:aff id="A2">Department of Obstetrics and Gynecology, School of Medicine, Box 356460, University of Washington, Seattle, WA</nlm:aff></affiliation></author><author><name sortKey="Millar, Robert P" sort="Millar, Robert P" uniqKey="Millar R" first="Robert P." last="Millar">Robert P. Millar</name><affiliation><nlm:aff id="A1">MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.</nlm:aff></affiliation><affiliation><nlm:aff id="A7">Department of Medical Biochemistry, University of Cape Town, 7925, South Africa</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of neuroscience : the official journal of the Society for Neuroscience</title><idno type="ISSN">0270-6474</idno><idno type="eISSN">1529-2401</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">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 analogue also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the post-castration 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.</p></div></front></TEI><pmc article-type="research-article" xml:lang="EN"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8102140</journal-id><journal-id journal-id-type="pubmed-jr-id">5035</journal-id><journal-id journal-id-type="nlm-ta">J Neurosci</journal-id><journal-title>The Journal of neuroscience : the official journal of the Society for Neuroscience</journal-title><issn pub-type="ppub">0270-6474</issn><issn pub-type="epub">1529-2401</issn></journal-meta><article-meta><article-id pub-id-type="pmid">19321788</article-id><article-id pub-id-type="pmc">3035813</article-id><article-id pub-id-type="doi">10.1523/JNEUROSCI.5740-08.2009</article-id><article-id pub-id-type="manuscript">NIHMS104272</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Roseweir</surname><given-names>Antonia K.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kauffman</surname><given-names>Alexander S.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Jeremy T.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Guerriero</surname><given-names>Kathryn A.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Morgan</surname><given-names>Kevin</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Pielecka-Fortuna</surname><given-names>Justyna</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Pineda</surname><given-names>Rafael</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gottsch</surname><given-names>Michelle L.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Tena-Sempere</surname><given-names>Manuel</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Moenter</surname><given-names>Suzanne M.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Terasawa</surname><given-names>Ei</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Clarke</surname><given-names>Iain J.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Steiner</surname><given-names>Robert A.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Millar</surname><given-names>Robert P.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A7">7</xref><xref ref-type="corresp" rid="CR1">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ.</aff><aff id="A2"><label>2</label>Department of Obstetrics and Gynecology, School of Medicine, Box 356460, University of Washington, Seattle, WA</aff><aff id="A3"><label>3</label>Department of Physiology, PO Box 13F, Monash University, Victoria 3800, Australia.</aff><aff id="A4"><label>4</label>Wisconsin National Primate Centre & Department of Pediatrics, University of Wisconsin-Madison, WI 53715, USA</aff><aff id="A5"><label>5</label>Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, VA</aff><aff id="A6"><label>6</label>Physiology Section, University of Cordoba, 14004 Cordoba, Spain</aff><aff id="A7"><label>7</label>Department of Medical Biochemistry, University of Cape Town, 7925, South Africa</aff><author-notes><corresp id="CR1"><label>*</label>Address correspondence and reprint requests to: Robert P. Millar, MRC Human Reproductive Sciences Unit, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ. Tel No: +44(0)131 242 6240 E-Mail: <email>r.millar@hrsu.mrc.ac.uk</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>5</day><month>5</month><year>2009</year></pub-date><pub-date pub-type="ppub"><day>25</day><month>3</month><year>2009</year></pub-date><pub-date pub-type="pmc-release"><day>9</day><month>2</month><year>2011</year></pub-date><volume>29</volume><issue>12</issue><fpage>3920</fpage><lpage>3929</lpage><abstract><p id="P1">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 analogue also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the post-castration 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.</p></abstract><kwd-group><kwd>Kisspeptin</kwd><kwd>gpr-54</kwd><kwd>antagonists</kwd><kwd>steroid feedback</kwd><kwd>GnRH</kwd><kwd>LH</kwd></kwd-group><contract-num rid="HD1">U54 HD012629-190008
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