[en] G protein-coupled receptors (GPCRs) carry out the majority of cellular transmembrane signaling. Many pathologies have underlying GPCR mutations, most of which cause misfolding and GPCR cell surface trafficking failure. Large libraries of existing small molecule GPCR ligands could be repurposed as pharmacological chaperones (PCs) which restore mutant GPCR folding and function, presenting an exciting alternative to complex gene repair, yet such in vivo studies are limited. Therefore, as proof-of-concept, we use one such known ligand/PC, Org42599/Org43553, to show functional rescue in mice bearing an inactivating human luteinizing hormone receptor (LHR) mutation. Mutant males had delayed puberty and Leydig cell LHR signaling impairment, however, fertility was unaffected. Mutant females had irregular estrous cycles, anovulation, abrogated ovarian LHR signaling, and complete infertility. PC treatment of mutant females restored LH signaling and estrous cyclicity. To characterize treatment efficacy, we developed an AI algorithm that reliably identified inherent differences among experimental groups, enabling functional analysis of the treatment effect in vivo. Our data set the stage to integrate AI analysis with GPCR-targeting PC molecules to treat diverse GPCR-based diseases.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Das, Debajyoti ; Department of Pharmacology, Center for Molecular Signaling (PZMS), Center for Gender-Specific Biology and Medicine (CGBM), Saarland University School of Medicine, 66421, Homburg, Germany
Wyatt, Amanda ; Department of Pharmacology, Center for Molecular Signaling (PZMS), Center for Gender-Specific Biology and Medicine (CGBM), Saarland University School of Medicine, 66421, Homburg, Germany
Sivaprasad, Sarath; CISPA Helmholtz Center for Information Security, 66123, Saarbrücken, Germany
Wahl, Vanessa ; Department of Pharmacology, Center for Molecular Signaling (PZMS), Center for Gender-Specific Biology and Medicine (CGBM), Saarland University School of Medicine, 66421, Homburg, Germany
Qiao, Sen; Department of Pharmacology, Center for Molecular Signaling (PZMS), Center for Gender-Specific Biology and Medicine (CGBM), Saarland University School of Medicine, 66421, Homburg, Germany
Ectors, Fabien ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Moosa, Zulfiah M; Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, 0084, Pretoria, South Africa
Newton, Claire L ; Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, 0084, Pretoria, South Africa ; Deanery of Biomedical Sciences, University of Edinburgh, EH8 9XD, Edinburgh, UK
Fritz, Mario; CISPA Helmholtz Center for Information Security, 66123, Saarbrücken, Germany
Millar, Robert P ; Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, 0084, Pretoria, South Africa. bob.millar@up.ac.za ; Deanery of Biomedical Sciences, University of Edinburgh, EH8 9XD, Edinburgh, UK. bob.millar@up.ac.za ; Institute for Infectious Diseases and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, 7925, Cape Town, South Africa. bob.millar@up.ac.za
Boehm, Ulrich ; Department of Pharmacology, Center for Molecular Signaling (PZMS), Center for Gender-Specific Biology and Medicine (CGBM), Saarland University School of Medicine, 66421, Homburg, Germany. ulrich.boehm@uks.eu
Language :
English
Title :
Functional rescue and AI analysis of a human inactivating GPCR mutation using a small molecule
Publication date :
08 January 2026
Journal title :
EMBO Molecular Medicine
ISSN :
1757-4676
eISSN :
1757-4684
Publisher :
Springer Science and Business Media Deutschland GmbH, Germany
DFG - Deutsche Forschungsgemeinschaft COST - European Cooperation in Science and Technology
Funding text :
The authors thank Dr. Igor Gamayun and Dr. Samer Alasmi for technical assistance. This project was supported by the Deutsche Forschungsgemeinschaft (DFG) through grants to UB (SFB/TR 152 and SFB 894), the Harry Oppenheimer Trust through an award to RM, the South African National Research Foundation (NRF) through grants to RM (105824) and CN (94008), and COST action BM1105 to UB and RM. This project was supported by the Deutsche
Forschungsgemeinschaft (DFG) through grants to UB (SFB/TR 152 and SFB
894), the Harry Oppenheimer Trust through an award to RM, the South
African National Research Foundation (NRF) through grants to RM (105824)
and CN (94008), and COST action BM1105 to UB and RM.
Abdelhamid MHM Walschaerts M Ahmad G Mieusset R Bujan L Hamdi S Mild experimental increase in testis and epididymis temperature in men: effects on sperm morphology according to spermatogenesis stages Transl Androl Urol 2019 8 651 665 32038961 6987600 10.21037/tau.2019.11.18
Ahmed CM Dwyer BT Romashko A Van Adestine S Park EH Lou Z Welty D Josiah S Savinainen A Zhang B Lewin AS SRD005825 acts as a pharmacologic chaperone of opsin and promotes survival of photoreceptors in an animal model of autosomal dominant retinitis pigmentosa Transl Vis Sci Technol 2019 8 30 31857914 6910612 10.1167/tvst.8.6.30
Amir ED Davis KL Tadmor MD Simonds EF Levine JH Bendall SC Shenfeld DK Krishnaswamy S Nolan GP Pe’er D viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia Nat Biotechnol 2013 31 545 552 23685480 4076922 10.1038/nbt.2594 1:CAS:528:DC%2BC3sXnvVSisrs%3D
Babwah AV Uterine and placental KISS1 regulate pregnancy: what we know and the challenges that lie ahead Reproduction 2015 150 R121 R128 26183891 10.1530/REP-15-0252
Bahena-Alvarez D Rincon-Heredia R Millan-Aldaco D Fiordelisio T Hernandez-Cruz A Calcium signaling and expression of voltage-gated calcium channels in the mouse ovary throughout the estrous cycledagger Biol Reprod 2019 100 1018 1034 30496339 10.1093/biolre/ioy250
Becht E McInnes L Healy J Dutertre CA Kwok IWH Ng LG Ginhoux F Newell EW Dimensionality reduction for visualizing single-cell data using UMAP Nat Biotechnol 2019 37 38 44 10.1038/nbt.4314 1:CAS:528:DC%2BC1cXitl2isbrN
Bedford JM Effects of elevated temperature on the epididymis and testis: experimental studies Adv Exp Med Biol 1991 286 19 32 2042501 10.1007/978-1-4684-5913-5_3 1:STN:280:DyaK3M3ltlCguw%3D%3D
Bernier V Lagace M Bichet DG Bouvier M Pharmacological chaperones: potential treatment for conformational diseases Trends Endocrinol Metab 2004 15 222 228 15223052 10.1016/j.tem.2004.05.003 1:CAS:528:DC%2BD2cXlt1Whtrc%3D
Bernier V Morello JP Zarruk A Debrand N Salahpour A Lonergan M Arthus MF Laperriere A Brouard R Bouvier M Bichet DG Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus J Am Soc Nephrol 2006 17 232 243 16319185 10.1681/ASN.2005080854 1:CAS:528:DC%2BD28XhtF2jsr8%3D
Böhle M, Fritz M, Schiele B (2022) B-cos networks: alignment is all we need for interpretability. In: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition
Brands J Bravo S Jürgenliemke L Grätz L Schihada H Frechen F Alenfelder J Pfeil C Ohse PG Hiratsuka S et al. A molecular mechanism to diversify Ca2+ signaling downstream of Gs protein-coupled receptors Nat Commun 2024 15 39227390 11372221 10.1038/s41467-024-51991-6 1:CAS:528:DC%2BB2cXhvFemsrjO 7684
Breen SM Andric N Ping T Xie F Offermans S Gossen JA Ascoli M Ovulation involves the luteinizing hormone-dependent activation of G(q/11) in granulosa cells Mol Endocrinol 2013 27 1483 1491 23836924 3753423 10.1210/me.2013-1130 1:CAS:528:DC%2BC3sXhsVenurzJ
Candlish M De Angelis R Götz V Boehm U Gene targeting in neuroendocrinology Compr Physiol 2015 5 1645 1676 26426463 10.1002/j.2040-4603.2015.tb00661.x
Chen S Liu X Segaloff DL A novel cyclic adenosine 3’,5’-monophosphate-responsive element involved in the transcriptional regulation of the lutropin receptor gene in granulosa cells Mol Endocrinol 2000 14 1498 1508 10976926 1:CAS:528:DC%2BD3cXmt1Onu7o%3D
Chen Y Wang Z Wu Y He W Du J Cai S Gong F Lu G Lin G Dai C Case report: a novel heterozygous ZP3 deletion associated with empty follicle syndrome and abnormal follicular development Front Genet 2021 12 34093671 8170154 10.3389/fgene.2021.690070 690070
Conn PM Ulloa-Aguirre A Trafficking of G-protein-coupled receptors to the plasma membrane: insights for pharmacoperone drugs Trends Endocrinol Metab 2010 21 190 197 20005736 10.1016/j.tem.2009.11.003 1:CAS:528:DC%2BC3cXis1Shuro%3D
Conn PM Ulloa-Aguirre A Ito J Janovick JA G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo Pharmacol Rev 2007 59 225 250 17878512 10.1124/pr.59.3.2 1:CAS:528:DC%2BD2sXht1ahsr3J
Derkach KV Bakhtyukov AA Shpakov AA Dar’in DV Shpakov AO Specificity of heterotrimeric G protein regulation by human chorionic gonadotropin and low-molecular agonist of luteinizing hormone receptor Cell Tissue Biol 2017 11 475 482 10.1134/S1990519X17060037
Dosovitskiy A, Beyer L, Kolesnikov A, Weissenborn D, Zhai X, Unterthiner T, Dehghani M, Minderer M, Heigold G, Gelly S (2021) An image is worth 16x16 words: transformers for image recognition at scale. In: International Conference on Learning Representations
Egbert JR Fahey PG Reimer J Owen CM Evsikov AV Nikolaev VO Griesbeck O Ray RS Tolias AS Jaffe LA Follicle-stimulating hormone and luteinizing hormone increase Ca2+ in the granulosa cells of mouse ovarian follicles Biol Reprod 2019 101 433 444 31087036 7302518 10.1093/biolre/ioz085
Eisenberg ML Lipshultz LI Anogenital distance as a measure of human male fertility J Assist Reprod Genet 2015 32 479 484 25533333 10.1007/s10815-014-0410-1
Francou B Bouligand J Voican A Amazit L Trabado S Fagart J Meduri G Brailly-Tabard S Chanson P Lecomte P Guiochon-Mantel A Young J Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations PLoS One 2011 6 22031817 3198730 10.1371/journal.pone.0025614 1:CAS:528:DC%2BC3MXhsVKisLvF e25614
Gerrits M Mannaerts B Kramer H Addo S Hanssen R First evidence of ovulation induced by oral LH agonists in healthy female volunteers of reproductive age J Clin Endocrinol Metab 2013 98 1558 1566 23515453 10.1210/jc.2012-3404 1:CAS:528:DC%2BC3sXmtFeht70%3D
Guo M Xu Y Gruebele M Temperature dependence of protein folding kinetics in living cells Proc Natl Acad Sci USA 2012 109 17863 17867 22665776 3497798 10.1073/pnas.1201797109 1:CAS:528:DC%2BC38Xhsl2ktb3N
Handelsman DJ Walters KA Ly LP Simplified method to measure mouse fertility Endocrinology 2020 161 32645712 10.1210/endocr/bqaa114 bqaa114
Hauser AS Attwood MM Rask-Andersen M Schioth HB Gloriam DE Trends in GPCR drug discovery: new agents, targets and indications Nat Rev Drug Discov 2017 16 829 842 29075003 6882681 10.1038/nrd.2017.178 1:CAS:528:DC%2BC2sXhslansbzF
Hotchkiss AK Vandenbergh JG The anogenital distance index of mice (Mus musculus domesticus): an analysis Contemp Top Lab Anim Sci 2005 44 46 48 16050669 1:CAS:528:DC%2BD2MXms1KrtLg%3D
Janovick JA Stewart MD Jacob D Martin LD Deng JM Stewart CA Wang Y Cornea A Chavali L Lopez S et al. Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy Proc Natl Acad Sci USA 2013 110 21030 21035 24324164 3876212 10.1073/pnas.1315194110 1:CAS:528:DC%2BC2cXnsF2gsw%3D%3D
Katritch V Cherezov V Stevens RC Diversity and modularity of G protein-coupled receptor structures Trends Pharmacol Sci 2012 33 17 27 22032986 10.1016/j.tips.2011.09.003 1:CAS:528:DC%2BC38XovFeksQ%3D%3D
Kobak D Berens P The art of using t-SNE for single-cell transcriptomics Nat Commun 2019 10 31780648 6882829 10.1038/s41467-019-13056-x 5416
Kossack N Simoni M Richter-Unruh A Themmen AP Gromoll J Mutations in a novel, cryptic exon of the luteinizing hormone/chorionic gonadotropin receptor gene cause male pseudohermaphroditism PLoS Med 2008 5 e88 18433292 2323302 10.1371/journal.pmed.0050088
Kullback S Leibler RA On information and sufficiency Ann Math Stat 1951 22 79 86 10.1214/aoms/1177729694
Lukassen S Bosch E Ekici AB Winterpacht A Characterization of germ cell differentiation in the male mouse through single-cell RNA sequencing Sci Rep 2018 8 29695820 5916943 10.1038/s41598-018-24725-0 1:STN:280:DC%2BC1Mjmsleqsg%3D%3D 6521
MacQueen J (1967) Some methods for classification and analysis of multivariate observations. In: Proceedings of the Fifth Berkeley Symposium on Mathemathical Statistics and Probability
Mayer C Boehm U Female reproductive maturation in the absence of kisspeptin/GPR54 signaling Nat Neurosci 2011 14 704 710 21516099 10.1038/nn.2818 1:CAS:528:DC%2BC3MXltFyqsb8%3D
Mijnders M Kleizen B Braakman I Correcting CFTR folding defects by small-molecule correctors to cure cystic fibrosis Curr Opin Pharmacol 2017 34 83 90 29055231 10.1016/j.coph.2017.09.014 1:CAS:528:DC%2BC2sXhs1ais7nM
Milla CE Ratjen F Marigowda G Liu F Waltz D Rosenfeld M VX13-809-011 Part B Investigator Group Lumacaftor/ivacaftor in patients aged 6-11 years with cystic fibrosis and homozygous for F508del-CFTR Am J Respir Crit Care Med 2017 195 912 920 27805836 5440888 10.1164/rccm.201608-1754OC 1:CAS:528:DC%2BC1cXktFaktbs%3D
Neves SR Ram PT Iyengar R G protein pathways Science 2002 296 1636 1639 12040175 10.1126/science.1071550 1:CAS:528:DC%2BD38XktlChtrY%3D
Newton CL Anderson RC Katz AA Millar RP Loss-of-function mutations in the human luteinizing hormone receptor predominantly cause intracellular retention Endocrinology 2016 157 4364 4377 27533885 10.1210/en.2016-1104 1:CAS:528:DC%2BC2sXhtlSgu7c%3D
Newton CL Anderson RC Kreuchwig A Krause G Katz AA Millar RP Rescue of function of mutant luteinising hormone receptors with deficiencies in cell surface expression, hormone binding, and hormone signalling Neuroendocrinology 2021 111 451 464 32316022 10.1159/000508000 1:CAS:528:DC%2BB3MXhtVGnurvJ
Newton CL Whay AM McArdle CA Zhang M van Koppen CJ van de Lagemaat R Segaloff DL Millar RP Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist Proc Natl Acad Sci USA 2011 108 7172 7176 21482767 3084114 10.1073/pnas.1015723108 1:CAS:528:DC%2BC3MXlslyqt7k%3D
Nimri R Lebenthal Y Lazar L Chevrier L Phillip M Bar M Hernandez-Mora E de Roux N Gat-Yablonski G A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family J Clin Endocrinol Metab 2011 96 E536 E545 21193544 10.1210/jc.2010-1676 1:CAS:528:DC%2BC3MXjvFahtbk%3D
Novaira HJ Sonko ML Hoffman G Koo Y Ko C Wolfe A Radovick S Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism Mol Endocrinol 2014 28 225 238 24422632 10.1210/me.2013-1319
Oksche A Rosenthal W The molecular basis of nephrogenic diabetes insipidus J Mol Med (Berl) 1998 76 326 337 9587067 10.1007/s001090050224 1:CAS:528:DyaK1cXjtFaksro%3D
Ortega JT Parmar T Carmena-Bargueno M Perez-Sanchez H Jastrzebska B Flavonoids improve the stability and function of P23H rhodopsin slowing down the progression of retinitis pigmentosa in mice J Neurosci Res 2022 100 1063 1083 35165923 9615108 10.1002/jnr.25021 1:CAS:528:DC%2BB38XjslSjsro%3D
Papp E, Csermely P (2006) Chemical chaperones: mechanisms of action and potential use. Handb Exp Pharmacol 405–416
Paukert M Agarwal A Cha J Doze VA Kang JU Bergles DE Norepinephrine controls astroglial responsiveness to local circuit activity Neuron 2014 82 1263 1270 24945771 4080721 10.1016/j.neuron.2014.04.038 1:CAS:528:DC%2BC2cXhtVCju7vF
Radomsky T Anderson RC Millar RP Newton CL Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic-pituitary-gonadal axis J Neuroendocrinol 2024 36 e13418 38852954 10.1111/jne.13418 1:CAS:528:DC%2BB2cXhtlSrtbrF
Rajagopalan-Gupta RM Lamm ML Mukherjee S Rasenick MM Hunzicker-Dunn M Luteinizing hormone/choriogonadotropin receptor-mediated activation of heterotrimeric guanine nucleotide binding proteins in ovarian follicular membranes Endocrinology 1998 139 4547 4555 9794464 10.1210/endo.139.11.6302 1:CAS:528:DyaK1cXntFWlt7g%3D
Rene P Lanfray D Richard D Bouvier M Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity JCI Insight 2021 6 e132778 33434184 7934941
Sahni N Yi S Taipale M Fuxman Bass JI Coulombe-Huntington J Yang F Peng J Weile J Karras GI Wang Y et al. Widespread macromolecular interaction perturbations in human genetic disorders Cell 2015 161 647 660 25910212 4441215 10.1016/j.cell.2015.04.013 1:CAS:528:DC%2BC2MXnt1emtrY%3D
Schoneberg T Schulz A Biebermann H Hermsdorf T Rompler H Sangkuhl K Mutant G-protein-coupled receptors as a cause of human diseases Pharmacol Ther 2004 104 173 206 15556674 10.1016/j.pharmthera.2004.08.008
Selvaraju RR, Cogswell M, Das A, Vedantam R, Parikh D, Batra D (2017) Grad-CAM: Visual explanations from deep networks via gradient-based localization. In: Proceedings of the IEEE International Conference on Computer Vision
Su J Song Y Yang Y Li Z Zhao F Mao F Wang D Cao G Study on the changes of LHR, FSHR and AR with the development of testis cells in Hu sheep Anim Reprod Sci 2023 256 37541020 10.1016/j.anireprosci.2023.107306 1:CAS:528:DC%2BB3sXhs1GitbzP 107306
Sullivan SD Moenter SM Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder Proc Natl Acad Sci USA 2004 101 7129 7134 15096602 406477 10.1073/pnas.0308058101 1:CAS:528:DC%2BD2cXktFeqsb8%3D
Tao YX Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications Pharmacol Ther 2006 111 949 973 16616374 10.1016/j.pharmthera.2006.02.008 1:CAS:528:DC%2BD28Xns1SksLg%3D
Tao YX The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology Endocr Rev 2010 31 506 543 20190196 3365848 10.1210/er.2009-0037 1:CAS:528:DC%2BC3cXhsVCrurvJ
Thankamony A Pasterski V Ong KK Acerini CL Hughes IA Anogenital distance as a marker of androgen exposure in humans Andrology 2016 4 616 625 26846869 6225986 10.1111/andr.12156 1:CAS:528:DC%2BC28XhtFOkur7E
Ting JT, Lee BR, Chong P, Soler-Llavina G, Cobbs C, Koch C, Zeng H, Lein E (2018) Preparation of acute brain slices using an optimized N-methyl-D-glucamine protective recovery method. J Vis Exp 53825
Ulloa-Aguirre A Zarinan T Dias JA Conn PM Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function Mol Cell Endocrinol 2014 382 411 423 23806559 10.1016/j.mce.2013.06.024 1:CAS:528:DC%2BC3sXhtV2rtLbP
Ulloa-Aguirre A Zarinan T Gutierrez-Sagal R Tao YX Targeting trafficking as a therapeutic avenue for misfolded GPCRs leading to endocrine diseases Front Endocrinol (Lausanne) 2022 13 36093106 10.3389/fendo.2022.934685 934685
Ulloa-Aguirre A Zarinan T Jardon-Valadez E Misfolded G protein-coupled receptors and endocrine disease. Molecular mechanisms and therapeutic prospects Int J Mol Sci 2021 22 12329 34830210 8622668 10.3390/ijms222212329 1:CAS:528:DC%2BB3MXis1CitL%2FP
van de Lagemaat R Timmers CM Kelder J van Koppen C Mosselman S Hanssen RG Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor Hum Reprod 2009 24 640 648 19088107 10.1093/humrep/den412
Van der Maaten L, Hinton G (2008) Visualizing data using t-SNE. J Mach Learn Res 9:2579–2605
van Koppen CJ Zaman GJ Timmers CM Kelder J Mosselman S van de Lagemaat R Smit MJ Hanssen RG A signaling-selective, nanomolar potent allosteric low molecular weight agonist for the human luteinizing hormone receptor Naunyn Schmiedebergs Arch Pharmacol 2008 378 503 514 18551279 10.1007/s00210-008-0318-3
van Straten NC Schoonus-Gerritsma GG van Someren RG Draaijer J Adang AE Timmers CM Hanssen RG van Boeckel CA The first orally active low molecular weight agonists for the LH receptor: thienopyr(im)idines with therapeutic potential for ovulation induction Chembiochem 2002 3 1023 1026 12362369 10.1002/1439-7633(20021004)3:10<1023::AID-CBIC1023>3.0.CO;2-9
Varney MJ Benovic JL The role of G protein-coupled receptors and receptor kinases in pancreatic beta-cell function and diabetes Pharmacol Rev 2024 76 267 299 38351071 10877731 10.1124/pharmrev.123.001015 1:CAS:528:DC%2BB2MXltVyltr8%3D
Vockley J Andersson HC Antshel KM Braverman NE Burton BK Frazier DM Mitchell J Smith WE Thompson BH Berry SA et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline Genet Med 2014 16 188 200 24385074 10.1038/gim.2013.157 1:CAS:528:DC%2BC2cXmt1Wktrw%3D
Walters KA Allan CM Jimenez M Lim PR Davey RA Zajac JD Illingworth P Handelsman DJ Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility Endocrinology 2007 148 3674 3684 17463055 10.1210/en.2007-0248 1:CAS:528:DC%2BD2sXot1Oisbk%3D
Wen S Götze IN Mai O Schauer C Leinders-Zufall T Boehm U Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain Endocrinology 2011 152 1515 1526 21303944 10.1210/en.2010-1208 1:CAS:528:DC%2BC3MXkvVOkt70%3D
Williams SA Stanley P Premature ovarian failure in mice with oocytes lacking core 1-derived O-glycans and complex N-glycans Endocrinology 2011 152 1057 1066 21239444 3040049 10.1210/en.2010-0917 1:CAS:528:DC%2BC3MXktVGrsbk%3D
Yang D Zhou Q Labroska V Qin S Darbalaei S Wu Y Yuliantie E Xie L Tao H Cheng J et al. G protein-coupled receptors: structure- and function-based drug discovery Signal Transduct Target Ther 2021 6 7 33414387 7790836 10.1038/s41392-020-00435-w 1:CAS:528:DC%2BB3MXis1Kjtr4%3D
Yang H Wang Y Liu W He T Liao J Qian Z Zhao J Cong Z Sun D Liu Z et al. Genome-wide pan-GPCR cell libraries accelerate drug discovery Acta Pharm Sin B 2024 14 4296 4311 39525595 11544303 10.1016/j.apsb.2024.06.023 1:CAS:528:DC%2BB2cXhsFalu7%2FE
Yung Y Aviel-Ronen S Maman E Rubinstein N Avivi C Orvieto R Hourvitz A Localization of luteinizing hormone receptor protein in the human ovary Mol Hum Reprod 2014 20 844 849 24874553 10.1093/molehr/gau041 1:CAS:528:DC%2BC2cXhtlyku7vK
Zhang FP Hamalainen T Kaipia A Pakarinen P Huhtaniemi I Ontogeny of luteinizing hormone receptor gene expression in the rat testis Endocrinology 1994 134 2206 2213 8156923 10.1210/endo.134.5.8156923 1:CAS:528:DyaK2cXivFSnsL4%3D
Zhang FP Poutanen M Wilbertz J Huhtaniemi I Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice Mol Endocrinol 2001 15 172 183 11145748 10.1210/mend.15.1.0582 1:CAS:528:DC%2BD3MXktVKmuw%3D%3D
Zheng J Guo N Huang Y Guo X Wagner A High temperature delays and low temperature accelerates evolution of a new protein phenotype Nat Commun 2024 15 38553445 10980763 10.1038/s41467-024-46332-6 1:CAS:528:DC%2BB2cXotlWlsL4%3D 2495
