{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T02:38:02Z","timestamp":1770691082587,"version":"3.49.0"},"reference-count":166,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.<\/jats:p>","DOI":"10.3390\/ijms222212329","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T08:19:20Z","timestamp":1636964360000},"page":"12329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-3886","authenticated-orcid":false,"given":"Alfredo","family":"Ulloa-Aguirre","sequence":"first","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, Universidad Nacional Aut\u00f3noma de M\u00e9xico and Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n SZ, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Zari\u00f1\u00e1n","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, Universidad Nacional Aut\u00f3noma de M\u00e9xico and Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n SZ, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3701-429X","authenticated-orcid":false,"given":"Eduardo","family":"Jard\u00f3n-Valadez","sequence":"additional","affiliation":[{"name":"Departamento de Recursos de la Tierra, Universidad Aut\u00f3noma Metropolitana-Lerma, Lerma de Villada 52005, Estado de M\u00e9xico, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.addr.2007.06.002","article-title":"Visiting the ER: The endoplasmic reticulum as a target for therapeutics in traffic related diseases","volume":"59","author":"Aridor","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semcdb.2003.12.008","article-title":"Principles of protein folding, misfolding and aggregation","volume":"15","author":"Dobson","year":"2004","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1126\/science.1068408","article-title":"Molecular chaperones in the cytosol: From nascent chain to folded protein","volume":"295","author":"Hartl","year":"2002","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/nsmb.1591","article-title":"Converging concepts of protein folding in vitro and in vivo","volume":"16","author":"Hartl","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/nature02261","article-title":"Protein folding and misfolding","volume":"426","author":"Dobson","year":"2003","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.tem.2004.05.003","article-title":"Pharmacological chaperones: Potential treatment for conformational diseases","volume":"15","author":"Bernier","year":"2004","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_7","first-page":"973","article-title":"Targeting of G protein-coupled receptors to the plasma membrane in health and disease","volume":"14","author":"Conn","year":"2009","journal-title":"Front. Biosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1111\/j.1600-0854.2004.00232.x","article-title":"Pharmacologic Rescue of Conformationally-Defective Proteins: Implications for the Treatment of Human Disease","volume":"5","author":"Janovick","year":"2004","journal-title":"Traffic"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1152\/physrev.00029.2016","article-title":"Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases","volume":"98","author":"Tao","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.tem.2009.11.003","article-title":"Trafficking of G-protein-coupled receptors to the plasma membrane: Insights for pharmacoperone drugs","volume":"21","author":"Conn","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1083\/jcb.200312018","article-title":"Misfolding diverts CFTR from recycling to degradation: Quality control at early endosomes","volume":"164","author":"Sharma","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1042\/ETLS20180055","article-title":"Modulation of proteostasis and protein trafficking: A therapeutic avenue for misfolded G protein-coupled receptors causing disease in humans","volume":"3","author":"Janovick","year":"2019","journal-title":"Emerg. Top. Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1080\/17512433.2018.1480367","article-title":"Pharmacoperone drugs: Targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders","volume":"11","author":"Hou","year":"2018","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0197-0186(02)00196-1","article-title":"Neurodegenerative disorders of protein aggregation","volume":"43","author":"Shastry","year":"2003","journal-title":"Neurochem. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1172\/JCI0216781","article-title":"Protein aggregation in disease: A role for folding intermediates forming specific multimeric interactions","volume":"110","author":"Horwich","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1016\/j.bbadis.2018.06.004","article-title":"Misfolded rhodopsin mutants display variable aggregation properties","volume":"1864","author":"Gragg","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s00232-019-00078-1","article-title":"Rhodopsin oligomerization and aggregation","volume":"252","author":"Park","year":"2019","journal-title":"J. Membr. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S1462399407000361","article-title":"Chemical and pharmacological chaperones as new therapeutic agents","volume":"9","author":"Loo","year":"2007","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1089\/adt.2014.627","article-title":"Development of a Phenotypic High-Content Assay to Identify Pharmacoperone Drugs for the Treatment of Primary Hyperoxaluria Type 1 by High-Throughput Screening","volume":"13","author":"Madoux","year":"2015","journal-title":"ASSAY Drug Dev. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1681\/ASN.2005080854","article-title":"Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus","volume":"17","author":"Bernier","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.coph.2004.08.001","article-title":"Pharmacological chaperone action on G-protein-coupled receptors","volume":"4","author":"Bernier","year":"2004","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/B978-0-12-385952-5.00008-7","article-title":"Pharmacological Chaperones for Misfolded Gonadotropin-Releasing Hormone Receptors","volume":"62","author":"Conn","year":"2011","journal-title":"Adv. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.2174\/1389450117666160307143345","article-title":"Pharmacoperones as a New Therapeutic Approach: In Vitro Identification and In vivo Validation of Bioactive Molecules","volume":"17","author":"Conn","year":"2016","journal-title":"Curr. Drug Targets"},{"key":"ref_24","unstructured":"Conn, P.M. (1998). G protein-coupled receptors and the G protein family. Handbook of Physiology-Endocrinology: Section 7, Cellular Endocrinology, Oxford University Press."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1210\/endo.142.1.7919","article-title":"Minireview: Insights into G Protein-Coupled Receptor Function Using Molecular Models","volume":"142","author":"Gershengorn","year":"2001","journal-title":"Endocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/nrm2299","article-title":"Heterotrimeric G protein activation by G-protein-coupled receptors","volume":"9","author":"Oldham","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1146\/annurev.pharmtox.48.113006.094830","article-title":"Regulation of GPCRs by endocytic membrane trafficking and its potential implications","volume":"48","author":"Hanyaloglu","year":"2008","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Pey, A.L. (2020). Protein homeostasis and regulation of intreacellular trafficking of G protein-coupled receptors. Protein Homeostasis Diseases, Academic Press.","DOI":"10.1016\/B978-0-12-819132-3.00002-6"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1124\/mol.63.6.1256","article-title":"The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints","volume":"63","author":"Fredriksson","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"431","DOI":"10.3389\/fphar.2018.00431","article-title":"GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets","volume":"9","author":"Insel","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1124\/mol.117.111062","article-title":"G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?","volume":"93","author":"Sriram","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2013.11.005","article-title":"\u201cPharmacoperone\u201d: What\u2019s in a word?","volume":"83","author":"Conn","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.nephro.2006.07.010","article-title":"Nephrogenic diabetes insipidus","volume":"2","author":"Bichet","year":"2006","journal-title":"Nephrol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1124\/pr.59.3.2","article-title":"G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue In Vivo","volume":"59","author":"Conn","year":"2007","journal-title":"Pharmacol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1093\/hmg\/ddi329","article-title":"Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance","volume":"14","author":"Calebiro","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/B978-0-12-385952-5.00007-5","article-title":"Regulation of Stability and Trafficking of Calcium-Sensing Receptors by Pharmacologic Chaperones","volume":"62","author":"Huang","year":"2011","journal-title":"Adv. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mce.2005.04.012","article-title":"Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity","volume":"239","author":"Tao","year":"2005","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1210\/er.2009-0037","article-title":"The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology","volume":"31","author":"Tao","year":"2010","journal-title":"Endocr. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1210\/er.2013-1121","article-title":"Chaperoning G Protein-Coupled Receptors: From Cell Biology to Therapeutics","volume":"35","author":"Tao","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1210\/en.2003-0524","article-title":"Functional Characterization of Melanocortin-4 Receptor Mutations Associated with Childhood Obesity","volume":"144","author":"Tao","year":"2003","journal-title":"Endocrinology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.tem.2005.10.006","article-title":"Inherited ACTH insensitivity illuminates the mechanisms of ACTH action","volume":"16","author":"Clark","year":"2005","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.mce.2013.06.024","article-title":"Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function","volume":"382","author":"Zarinan","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_43","unstructured":"Huhtaniemi, I.M.L. (2019). Mutations of gonadotropin-releasing hormone receptor gene. Encyclopedia of Endocrine Diseases, Elsevier Inc.. [2nd ed.]."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Francou, B., Bouligand, J., Voican, A., Amazit, L., Trabado, S., Fagart, J., Meduri, G., Brailly-Tabard, S., Chanson, P., and LeComte, P. (2011). Normosmic Congenital Hypogonadotropic Hypogonadism Due to TAC3\/TACR3 Mutations: Characterization of Neuroendocrine Phenotypes and Novel Mutations. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025614"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/hmg\/ddn318","article-title":"PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity","volume":"18","author":"Monnier","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1210\/endo.152.1.9993","article-title":"A Novel Loss-of-Function Mutation in GPR54\/KISS1R Leads to Hypogonadotropic Hypogonadism in a Highly Consanguineous Family","volume":"152","author":"Nimri","year":"2011","journal-title":"Endocrinology"},{"key":"ref_47","first-page":"479","article-title":"Beyond the Signal Sequence: Protein Routing in Health and Disease","volume":"26","author":"Conn","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/S0165-6147(00)01575-3","article-title":"Pharmacological chaperones: A new twist on receptor folding","volume":"21","author":"Morello","year":"2000","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"157","DOI":"10.2165\/00063030-200721030-00003","article-title":"Pharmacological chaperones in nephrogenic diabetes insipidus: Possibilities for clinical application","volume":"21","author":"Robben","year":"2007","journal-title":"BioDrugs"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"F253","DOI":"10.1152\/ajprenal.00247.2006","article-title":"Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: Relevance to therapy of nephrogenic diabetes insipidus","volume":"292","author":"Robben","year":"2007","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1159\/000508000","article-title":"Rescue of Function of Mutant Luteinising Hormone Receptors with Deficiencies in Cell Surface Expression, Hormone Binding, and Hormone Signalling","volume":"111","author":"Newton","year":"2021","journal-title":"Neuroendocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7172","DOI":"10.1073\/pnas.1015723108","article-title":"Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist","volume":"108","author":"Newton","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"bqab134","DOI":"10.1210\/endocr\/bqab134","article-title":"Rescue of cell surface expression and signalling of mutant follicle-stimulating hormone receptors","volume":"162","author":"Hanyroup","year":"2021","journal-title":"Endocrinology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.mce.2008.09.015","article-title":"Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine","volume":"298","author":"Janovick","year":"2009","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fendo.2014.00131","article-title":"Ipsen 5i is a Novel Potent Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants","volume":"5","author":"Tao","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.anireprosci.2005.05.032","article-title":"GnRHs and GnRH receptors","volume":"88","author":"Millar","year":"2005","journal-title":"Anim. Reprod. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S1472-6483(10)61901-3","article-title":"Biochemical and functional aspects of gonadotrophin-releasing hormone and gonadotrophins","volume":"1","author":"Timossi","year":"2000","journal-title":"Reprod. Biomed. Online"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1210\/er.2003-0002","article-title":"Gonadotropin-releasing hormone receptors","volume":"25","author":"Millar","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1210\/mend.12.2.0056","article-title":"Addition of catfish gonadotropin-releasing hormone (GnRH) receptor intracellular carboxyl-terminal tail to rat GnRH receptor alters receptor expression and regulation","volume":"12","author":"Lin","year":"1998","journal-title":"Mol. Endocrinol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0303-7207(99)00024-6","article-title":"The tail of the gonadotrophin-releasing hormone receptor: Desensitization at, and distal to, G protein-coupled receptors","volume":"151","author":"McArdle","year":"1999","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1385\/ENDO:22:3:317","article-title":"Evolved Regulation of Gonadotropin-Releasing Hormone Receptor Cell Surface Expression","volume":"22","author":"Janovick","year":"2003","journal-title":"Endocrine"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"12010","DOI":"10.1074\/jbc.M600548200","article-title":"Genetic Analysis of the First and Third Extracellular Loops of the C5a Receptor Reveals an Essential WXFG Motif in the First Loop","volume":"281","author":"Klco","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.mce.2011.01.016","article-title":"Biochemical mechanism of pathogenesis of human gonadotropin-releasing hormone receptor mutants Thr104Ile and Tyr108Cys associated with familial hypogonadotropic hypogonadism","volume":"337","author":"Janovick","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/cb600360h","article-title":"G-Protein-Coupled Receptor Trafficking: Understanding the Chemical Basis of Health and Disease","volume":"1","author":"Janovick","year":"2006","journal-title":"ACS Chem. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1210\/mend.13.6.0291","article-title":"Influence of a species-specific extracellular amino acid on expression and function of the human gonadotropin-releasing hormone receptor","volume":"13","author":"Arora","year":"1999","journal-title":"Mol. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1210\/me.2006-0066","article-title":"Protein Folding as Posttranslational Regulation: Evolution of a Mechanism for Controlled Plasma Membrane Expression of a G Protein-Coupled Receptor","volume":"20","author":"Conn","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"24506","DOI":"10.1074\/jbc.M501978200","article-title":"Parallel Regulation of Membrane Trafficking and Dominant-negative Effects by Misrouted Gonadotropin-releasing Hormone Receptor Mutants","volume":"280","author":"Knollman","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_68","first-page":"1580","article-title":"Prevalence, Phenotypic Spectrum, and Modes of Inheritance of Gonadotropin-Releasing Hormone Receptor Mutations in Idiopathic Hypogonadotropic Hypogonadism1","volume":"86","author":"Beranova","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"8417","DOI":"10.1074\/jbc.M510601200","article-title":"Regulation of G protein-coupled receptor trafficking by inefficient plasma membrane expression: Molecular basis of an evolved strategy","volume":"281","author":"Janovick","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4825","DOI":"10.1210\/jc.2002-020961","article-title":"Receptor-Misrouting: An Unexpectedly Prevalent and Rescuable Etiology in Gonadotropin-Releasing Hormone Receptor-Mediated Hypogonadotropic Hypogonadism","volume":"87","author":"Janovick","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1124\/jpet.102.048454","article-title":"Structure-Activity Relations of Successful Pharmacologic Chaperones for Rescue of Naturally Occurring and Manufactured Mutants of the Gonadotropin-Releasing Hormone Receptor","volume":"305","author":"Janovick","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1210\/jcem.87.5.8386","article-title":"Molecular Basis of Hypogonadotropic Hypogonadism: Restoration of Mutant (E 90 K) GnRH Receptor Function by a Deletion at a Distant Site","volume":"87","author":"Janovick","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.phrs.2013.12.004","article-title":"Transitioning pharmacoperones to therapeutic use: In vivo proof-of-principle and design of high throughput screens","volume":"83","author":"Conn","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"21030","DOI":"10.1073\/pnas.1315194110","article-title":"Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy","volume":"110","author":"Janovick","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4454","DOI":"10.1073\/pnas.0914261107","article-title":"Salt bridge integrates GPCR activation with protein trafficking","volume":"107","author":"Janovick","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1677\/JOE-08-0527","article-title":"Conformational effects of Lys191 in the human GnRH receptor: Mutagenesis and molecular dynamics simulations studies","volume":"201","author":"Pineiro","year":"2009","journal-title":"J. Endocrinol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1046\/j.1365-2265.2001.01211.x","article-title":"A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene","volume":"54","author":"Soderlund","year":"2001","journal-title":"Clin. Endocrinol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1210\/me.2004-0091","article-title":"Human Loss-of-Function Gonadotropin-Releasing Hormone Receptor Mutants Retain Wild-Type Receptors in the Endoplasmic Reticulum: Molecular Basis of the Dominant-Negative Effect","volume":"18","author":"Brothers","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1530\/eje.1.02198","article-title":"Two novel GnRHR gene mutations in two siblings with hypogonadotropic hypogonadism","volume":"155","author":"Antelli","year":"2006","journal-title":"Eur. J. Endocrinol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1210\/endo.138.7.5233","article-title":"An Intramolecular Disulfide Bond between Conserved Extracellular Cysteines in the Gonadotropin-Releasing Hormone Receptor Is Essential for Binding and Activation1","volume":"138","author":"Cook","year":"1997","journal-title":"Endocrinology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.tips.2009.02.002","article-title":"Drug development and the cellular quality control system","volume":"30","author":"Conn","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"23171","DOI":"10.1074\/jbc.M610896200","article-title":"Opioid receptor pharmacological chaperones act by binding and stabilizing newly synthesized receptors in the endoplasmic reticulum","volume":"282","author":"Leskela","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4416","DOI":"10.1074\/jbc.M007151200","article-title":"Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome","volume":"276","author":"Hogue","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"13727","DOI":"10.1074\/jbc.275.18.13727","article-title":"Export from the endoplasmic reticulum represents the limiting step in the maturation and cell surface expression of the human delta opioid receptor","volume":"275","author":"Hogue","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.phrs.2013.12.001","article-title":"Targeting opioid receptors with pharmacological chaperones","volume":"83","author":"Lackman","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"26622","DOI":"10.1074\/jbc.M413815200","article-title":"Inefficient maturation of the rat luteinizing hormone receptor. A putative way to regulate receptor numbers at the cell surface","volume":"280","author":"Pietila","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1210\/edrv.23.2.0462","article-title":"The lutropin\/choriogonadotropin receptor, a 2002 perspective","volume":"23","author":"Ascoli","year":"2002","journal-title":"Endocr. Rev."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1172\/JCI41350","article-title":"The ovary: Basic biology and clinical implications","volume":"120","author":"Richards","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_89","first-page":"739","article-title":"The Follicle-Stimulating Hormone Receptor: Biochemistry, Molecular Biology, Physiology, and Pathophysiology","volume":"18","author":"Simoni","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_90","first-page":"468","article-title":"A short evolutionary history of FSH-stimulated spermatogenesis","volume":"14","author":"Huhtaniemi","year":"2015","journal-title":"Hormones"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1210\/edrv-15-5-574","article-title":"Leydig cells: Endocrine, paracrine, and autocrine regulation","volume":"15","author":"Saez","year":"1994","journal-title":"Endocr. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.mce.2006.01.019","article-title":"Ligand-selective determinants in gonadotropin receptors","volume":"260\u2013262","author":"Bogerd","year":"2007","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3401","DOI":"10.1210\/en.2008-1800","article-title":"A Monoclonal Antibody with Thyrotropin (TSH) Receptor Inverse Agonist and TSH Antagonist Activities Binds to the Receptor Hinge Region as Well as to the Leucine-Rich Domain","volume":"150","author":"Chen","year":"2009","journal-title":"Endocrinology"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Krause, G., Kreuchwig, A., and Kleinau, G. (2012). Extended and Structurally Supported Insights into Extracellular Hormone Binding, Signal Transduction and Organization of the Thyrotropin Receptor. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052920"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Majumdar, R., and Dighe, R.R. (2012). The Hinge Region of Human Thyroid-Stimulating Hormone (TSH) Receptor Operates as a Tunable Switch between Hormone Binding and Receptor Activation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040291"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"12491","DOI":"10.1073\/pnas.1206643109","article-title":"Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor","volume":"109","author":"Jiang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.mce.2013.08.021","article-title":"Structural biology of glycoprotein hormones and their receptors: Insights to signaling","volume":"382","author":"Jiang","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1210\/er.2008-0044","article-title":"Thyrotropin and Homologous Glycoprotein Hormone Receptors: Structural and Functional Aspects of Extracellular Signaling Mechanisms","volume":"30","author":"Kleinau","year":"2009","journal-title":"Endocr. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0083-6729(02)64008-7","article-title":"Molecular, structural, and cellular biology of follitropin and follitropin receptor","volume":"64","author":"Dias","year":"2002","journal-title":"Vitam. Horm."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"30741","DOI":"10.1074\/jbc.M313881200","article-title":"A Conserved Motif for the Transport of G Protein-coupled Receptors from the Endoplasmic Reticulum to the Cell Surface","volume":"279","author":"Duvernay","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mce.2004.06.004","article-title":"Functional significance of the BBXXB motif reversed present in the cytoplasmic domains of the human follicle-stimulating hormone receptor","volume":"223","author":"Timossi","year":"2004","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_102","first-page":"1","article-title":"Intracellular Trafficking of Gonadotropin Receptors in Health and Disease","volume":"245","author":"Zarinan","year":"2018","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3020","DOI":"10.1210\/en.2018-00452","article-title":"FSH Receptor Signaling: Complexity of Interactions and Signal Diversity","volume":"159","author":"Reiter","year":"2018","journal-title":"Endocrinology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3487","DOI":"10.1007\/s00018-009-0134-z","article-title":"Developmental regulation of p70 S6 kinase by a G protein-coupled receptor dynamically modelized in primary cells","volume":"66","author":"Musnier","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1530\/eje.0.1470597","article-title":"Homozygous mutation within the conserved Ala-Phe-Asn-Glu-Thr motif of exon 7 of the LH receptor causes male pseudohermaphroditism","volume":"147","author":"Gromoll","year":"2002","journal-title":"Eur. J. Endocrinol."},{"key":"ref_106","first-page":"3722","article-title":"Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene","volume":"81","author":"Aittomaki","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1385\/ENDO:26:3:207","article-title":"Mutations in Human Gonadotropin and Gonadotropin-Receptor Genes","volume":"26","author":"Huhtaniemi","year":"2005","journal-title":"Endocrine"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1124\/mol.116.104398","article-title":"The Follitropin Receptor: Matching Structure and Function","volume":"90","author":"Zarinan","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Althumairy, D., Zhang, X., Baez, N., Barisas, G., Roess, D.A., Bousfield, G.R., and Crans, D.C. (2020). Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors. Diseases, 8.","DOI":"10.3390\/diseases8030035"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"4364","DOI":"10.1210\/en.2016-1104","article-title":"Loss-of-Function Mutations in the Human Luteinizing Hormone Receptor Predominantly Cause Intracellular Retention","volume":"157","author":"Newton","year":"2016","journal-title":"Endocrinology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1210\/jcem.87.6.8523","article-title":"Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig cell hypoplasia: Abnormal processing causes signaling deficiency","volume":"87","author":"Martens","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1210\/me.2003-0406","article-title":"Intracellularly Located Misfolded Glycoprotein Hormone Receptors Associate with Different Chaperone Proteins than Their Cognate Wild-Type Receptors","volume":"18","author":"Mizrachi","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"R235","DOI":"10.1530\/REP-13-0351","article-title":"Mutations and polymorphisms in FSH receptor: Functional implications in human reproduction","volume":"146","author":"Desai","year":"2013","journal-title":"Reproduction"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/S1472-6483(10)60529-9","article-title":"Mutations along the hypothalamic\u2013pituitary\u2013gonadal axis affecting male reproduction","volume":"15","author":"Huhtaniemi","year":"2007","journal-title":"Reprod. Biomed. Online"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e534","DOI":"10.1210\/clinem\/dgaa782","article-title":"A Novel Mutation in the FSH Receptor (I423T) Affecting Receptor Activation and Leading to Primary Ovarian Failure","volume":"106","author":"Zarinan","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_116","first-page":"9","article-title":"Inherited primary amenorrhea. The first gynecological disease of Finnish heritage","volume":"112","author":"Aittomaki","year":"1996","journal-title":"Duodecim"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/ng0297-205","article-title":"Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility","volume":"15","author":"Tapanainen","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1210\/jc.2003-030217","article-title":"Delayed Puberty and Primary Amenorrhea Associated with a Novel Mutation of the Human Follicle-Stimulating Hormone Receptor: Clinical, Histological, and Molecular Studies","volume":"88","author":"Meduri","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1093\/molehr\/8.4.311","article-title":"Functional characterization of the human FSH receptor with an inactivating Ala189Val mutation","volume":"8","author":"Rannikko","year":"2002","journal-title":"Mol. Hum. Reprod."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.mce.2010.08.016","article-title":"Preferential beta-arrestin signalling at low receptor density revealed by functional characterization of the human FSH receptor A189 V mutation","volume":"331","author":"Tranchant","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0303-7207(96)03949-4","article-title":"Functional and clinical consequences of mutations in the FSH receptor","volume":"125","author":"Gromoll","year":"1996","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Jardon-Valadez, E., Castillo-Guajardo, D., Martinez-Luis, I., Gutierrez-Sagal, R., Zarinan, T., and Ulloa-Aguirre, A. (2018). Molecular dynamics simulation of the follicle-stimulating hormone receptor. Understanding the conformational dynamics of receptor variants at positions N680 and D408 from in silico analysis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0207526"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1093\/humrep\/dew025","article-title":"A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: A fertility application of whole exome sequencing","volume":"31","author":"Bramble","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"031910","DOI":"10.1103\/PhysRevE.65.031910","article-title":"Convergence of sampling in protein simulations","volume":"65","author":"Hess","year":"2002","journal-title":"Phys. Rev. E Stat. Nonlinear Soft Matter Phys."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1016\/S0140-6736(09)60327-5","article-title":"Cystic fibrosis","volume":"373","author":"Freedman","year":"2009","journal-title":"Lancet"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"595","DOI":"10.4187\/aarc0427","article-title":"Cystic Fibrosis: Pathogenesis and Future Treatment Strategies","volume":"54","author":"Ratjen","year":"2009","journal-title":"Respir. Care"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1016\/0092-8674(93)90353-R","article-title":"Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis","volume":"73","author":"Welsh","year":"1993","journal-title":"Cell"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1172\/JCI119302","article-title":"Correcting temperature-sensitive protein folding defects","volume":"99","author":"Brown","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1210\/endo.138.1.4902","article-title":"Temperature Sensitivity of Some Mutants of the Lutropin\/Choriogonadotropin Receptor 1","volume":"138","author":"Jaquette","year":"1997","journal-title":"Endocrinology"},{"key":"ref_130","first-page":"346","article-title":"Modulation of \u03b12C adrenergic receptor temperature-sensitive trafficking by HSP90","volume":"1813","author":"Filipeanu","year":"2011","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Bioenerg."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/978-94-007-4765-4_14","article-title":"Pharmacological Chaperones Correct Misfolded GPCRs and Rescue Function: Protein Trafficking as a Therapeutic Target","volume":"63","author":"Janovick","year":"2012","journal-title":"Subcell. Biochem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/humupd\/dmh015","article-title":"Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism","volume":"10","author":"Janovick","year":"2004","journal-title":"Hum. Reprod. Update"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1385\/ENDO:13:3:401","article-title":"Combined Modification of Intracellular and Extracellular Loci on Human Gonadotropin-Releasing Hormone Receptor Provides a Mechanism for Enhanced Expression","volume":"13","author":"Janovick","year":"2000","journal-title":"Endocrine"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1677\/jme.1.02142","article-title":"Calnexin regulated gonadotropin-releasing hormone receptor plasma membrane expression","volume":"37","author":"Brothers","year":"2006","journal-title":"J. Mol. Endocrinol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"5961","DOI":"10.1073\/pnas.0911991107","article-title":"Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP\/Grp78","volume":"107","author":"Gorbatyuk","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"20676","DOI":"10.1074\/jbc.M611530200","article-title":"Rescue of a Nephrogenic Diabetes Insipidus-causing Vasopressin V2 Receptor Mutant by Cell-penetrating Peptides","volume":"282","author":"Oueslati","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/j.bbapap.2006.08.012","article-title":"Small molecule pharmacological chaperones: From thermodynamic stabilization to pharmaceutical drugs","volume":"1764","author":"Arakawa","year":"2006","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Proteins Proteom."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1203\/00006450-200212000-00004","article-title":"Chemical chaperones: A pharmacological strategy for disorders of protein folding and trafficking","volume":"52","author":"Perlmutter","year":"2002","journal-title":"Pediatr. Res."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Janovick, J.A., Park, B.S., and Conn, P.M. (2011). Therapeutic Rescue of Misfolded Mutants: Validation of Primary High Throughput Screens for Identification of Pharmacoperone Drugs. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022784"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.1210\/jc.2004-2071","article-title":"In Vitro Coexpression and Pharmacological Rescue of Mutant Gonadotropin-Releasing Hormone Receptors Causing Hypogonadotropic Hypogonadism in Humans Expressing Compound Heterozygous Alleles","volume":"90","author":"Janovick","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"3360","DOI":"10.1210\/jc.2003-030084","article-title":"Dominant-Negative Action of Disease-Causing Gonadotropin-Releasing Hormone Receptor (GnRHR) Mutants: A Trait That Potentially Coevolved with Decreased Plasma Membrane Expression of GnRHR in Humans","volume":"88","author":"Ji","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1172\/JCI8688","article-title":"Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants","volume":"105","author":"Morello","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"14442","DOI":"10.1074\/jbc.M300087200","article-title":"Pharmacological Chaperone-mediated In Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa","volume":"278","author":"Noorwez","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1172\/JCI119788","article-title":"In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR","volume":"100","author":"Rubenstein","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"47254","DOI":"10.1074\/jbc.M408154200","article-title":"Pharmacochaperones Post-translationally Enhance Cell Surface Expression by Increasing Conformational Stability of Wild-Type and Mutant Vasopressin V2 Receptors","volume":"279","author":"Wuller","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1093\/hmg\/ddh105","article-title":"Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo","volume":"13","author":"Sangkuhl","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1172\/JCI7866","article-title":"Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice","volume":"104","author":"Cordier","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3109\/10606820212134","article-title":"V2R structure and diabetes insipidus","volume":"8","author":"Birnbaumer","year":"2002","journal-title":"Recept. Channels"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1124\/jpet.105.097725","article-title":"Peripheral Administration of a Melanocortin 4-Receptor Inverse Agonist Prevents Loss of Lean Body Mass in Tumor-Bearing Mice","volume":"317","author":"Nicholson","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1021\/jm034244g","article-title":"Identification of 2-{2-[2-(5-Bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl}-4,5-dihydro-1H-imidazole (ML00253764), a Small Molecule Melanocortin 4 Receptor Antagonist That Effectively Reduces Tumor-Induced Weight Loss in a Mouse Model","volume":"47","author":"Vos","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1111\/j.1582-4934.2009.00726.x","article-title":"Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients","volume":"13","author":"Fan","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"817","DOI":"10.7150\/ijbs.9625","article-title":"A Small Molecule Agonist THIQ as a Novel Pharmacoperone for Intracellularly Retained Melanocortin-4 Receptor Mutants","volume":"10","author":"Huang","year":"2014","journal-title":"Int. J. Biol. Sci."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"21712","DOI":"10.1074\/jbc.M702285200","article-title":"Contribution of the conserved amino acids of the melanocortin-4 receptor in [corrected] [Nle4,D-Phe7]-alpha-melanocyte-stimulating [corrected] hormone binding and signaling","volume":"282","author":"Chen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"19854","DOI":"10.1074\/jbc.M110.124792","article-title":"Calcium-sensing Receptor Biosynthesis Includes a Cotranslational Conformational Checkpoint and Endoplasmic Reticulum Retention","volume":"285","author":"Cavanaugh","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"9517","DOI":"10.1074\/jbc.M609045200","article-title":"Rescue of Calcium-sensing Receptor Mutants by Allosteric Modulators Reveals a Conformational Checkpoint in Receptor Biogenesis","volume":"282","author":"Huang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.phrs.2014.01.005","article-title":"Pharmacological chaperoning: A primer on mechanism and pharmacology","volume":"83","author":"Leidenheimer","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1210\/me.2009-0041","article-title":"Pharmacochaperone-Mediated Rescue of Calcium-Sensing Receptor Loss-of-Function Mutants","volume":"23","author":"White","year":"2009","journal-title":"Mol. Endocrinol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"15518","DOI":"10.1074\/jbc.M114.556381","article-title":"Functional Rescue of Kallmann Syndrome-associated Prokineticin Receptor 2 (PKR2) Mutants Deficient in Trafficking","volume":"289","author":"Chen","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fendo.2011.00006","article-title":"Pharmacoperone identification for therapeutic rescue of misfolded mutant proteins","volume":"2","author":"Conn","year":"2011","journal-title":"Front. Endocrinol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1210\/me.2008-0384","article-title":"Molecular mechanism of action of pharmacoperone rescue of misrouted GPCR mutants: The GnRH receptor","volume":"23","author":"Janovick","year":"2009","journal-title":"Mol. Endocrinol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1210\/me.2012-1072","article-title":"Mice harboring Gnrhr E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure","volume":"26","author":"Stewart","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1177\/1087057113483559","article-title":"High-Throughput Screen for Pharmacoperones of the Vasopressin Type 2 Receptor","volume":"18","author":"Conn","year":"2013","journal-title":"J. Biomol. Screen."},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Pey, A.L. (2020). Cellular high-throughput screening. Protein Homeostasis Deseases, Academic Press.","DOI":"10.1016\/B978-0-12-819132-3.00002-6"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.jmb.2009.11.015","article-title":"Molecular mechanisms of rhodopsin retinitis pigmentosa and the efficacy of pharmacological rescue","volume":"395","author":"Krebs","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.1167\/iovs.07-1539","article-title":"A High-Throughput Screening Method for Small-Molecule Pharmacologic Chaperones of Misfolded Rhodopsin","volume":"49","author":"Noorwez","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"2858","DOI":"10.1172\/JCI34355","article-title":"Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria","volume":"118","author":"Pey","year":"2008","journal-title":"J. Clin. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12329\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:32Z","timestamp":1760167832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12329"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":166,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212329"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212329","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]}}}