{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:47:49Z","timestamp":1787017669681,"version":"build-2736575974"},"reference-count":46,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2013,7,1]]},"abstract":"<jats:p>\n                    The human GnRH receptor (GNRHR1) has a specific set of properties with physiological and pharmacological influences not appropriately modeled in laboratory animals or cell-based systems. To address this deficiency, we have generated human GNRHR1 knock-in mice and described their reproductive phenotype. Measurement of pituitary GNRHR1 transcripts from homozygous human GNRHR1 knock-in ( ki\/ ki) mice revealed a severe reduction (7- to 8-fold) compared with the mouse Gnrhr1 in wild-type mice.\n                    <jats:sup>125<\/jats:sup>\n                    I-GnRH binding assays on pituitary membrane fractions corroborated reduced human GNRHR1 protein expression in ki\/ ki mice, as occurs with transfection of human GNRHR1 in cell lines. Female homozygous knock-in mice displayed normal pubertal onset, indicating that a large reduction in GNRHR1 expression is sufficient for this process. However, ki\/ ki females exhibited periods of prolonged estrous and\/or metestrous and reduced fertility. No impairment was found in reproductive maturity or adult fertility in male ki\/ ki mice. Interestingly, the serum LH response to GnRH challenge was reduced in both knock-in males and females, indicating a reduced GNRHR1 signaling capacity. Small molecules targeting human GPCRs usually have poor activities at homologous rodent receptors, thus limiting their use in preclinical development. Therefore, we tested a human-specific GnRH1 antagonist, NBI-42902, in our mouse model and demonstrated abrogation of a GnRH1-induced serum LH rise in ki\/ ki mice and an absence of effect in littermates expressing the wild-type murine receptor. This novel model provides the opportunity to study the human receptor in vivo and for screening the activity of human-specific GnRH analogs.\n                  <\/jats:p>","DOI":"10.1152\/ajpendo.00624.2012","type":"journal-article","created":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T22:32:37Z","timestamp":1367447557000},"page":"E67-E77","source":"Crossref","is-referenced-by-count":6,"title":["Reproductive physiology of a humanized GnRH receptor mouse model: application in evaluation of human-specific analogs"],"prefix":"10.1152","volume":"305","author":[{"given":"Javier A.","family":"Tello","sequence":"first","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trudy","family":"Kohout","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Neurocrine Biosciences, Inc., San Diego, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Pineda","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology, and Immunology, University of C\u00f3rdoba, C\u00f3rdoba, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Maki","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Neurocrine Biosciences, Inc., San Diego, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Scott Struthers","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Neurocrine Biosciences, Inc., San Diego, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Millar","sequence":"additional","affiliation":[{"name":"Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom;"},{"name":"University of Cape Town\/Medical Research Council Receptor Biology Unit, University of Cape Town, Cape Town, South Africa; and"},{"name":"Mammal Research Institute, University of Pretoria, Pretoria, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2004-0091"},{"key":"B2","first-page":"2366","volume":"358","author":"Carel JC","year":"2008","journal-title":"Curr Ther Endocrinol Metab"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.04.018"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2008.10.051"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1124\/pr.59.3.2"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2009.11.003"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/me.2011-1247"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/BF02738686"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(94)03449-4"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1210\/endo.140.4.6780"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod56.1.160"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/mend.11.12.0020"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1677\/JOE-07-0471"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.240341"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1006\/hbeh.1997.1387"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-1139"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914261107"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510601200"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.7.8582"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1385\/ENDO:22:3:317"},{"key":"B21","volume-title":"Knobil and Neill's Physiology of Reproduction","author":"Knobil E","year":"2006"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501978200"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2011.78"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/er.2003-0002"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.anireprosci.2005.05.032"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2411"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deq183"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod30.3.556"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3369-06.2006"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0840"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-011-1358-9"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/BF02069557"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.07067"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.108.075259"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1210\/endo-115-6-2484"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-2-11"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2003.12.014"},{"key":"B39","volume-title":"Yen & Jaffe's Reproductive Endocrinology E-Book","author":"Strauss JF","year":"2009"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2012.03.002"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1530\/REP-11-0239"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmh015"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2011.01175.x"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1210\/mend.13.4.0262"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod31.5.1007"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-1949"}],"container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpendo.00624.2012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T16:05:38Z","timestamp":1567958738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpendo.00624.2012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,7,1]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,7,1]]}},"alternative-id":["10.1152\/ajpendo.00624.2012"],"URL":"https:\/\/doi.org\/10.1152\/ajpendo.00624.2012","relation":{},"ISSN":["0193-1849","1522-1555"],"issn-type":[{"value":"0193-1849","type":"print"},{"value":"1522-1555","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,7,1]]}}}