{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T15:59:19Z","timestamp":1770825559758,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["Thuthuka 117679"],"award-info":[{"award-number":["Thuthuka 117679"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["Competitive Support for Unrated Researchers 94008"],"award-info":[{"award-number":["Competitive Support for Unrated Researchers 94008"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["Swiss-South African Joint Research Programme 87393"],"award-info":[{"award-number":["Swiss-South African Joint Research Programme 87393"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["Competitive Support for Rated Researchers 105824"],"award-info":[{"award-number":["Competitive Support for Rated Researchers 105824"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["National Equipment Program"],"award-info":[{"award-number":["National Equipment Program"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37HD019938"],"award-info":[{"award-number":["R37HD019938"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD082314"],"award-info":[{"award-number":["R01HD082314"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21HD098684"],"award-info":[{"award-number":["R21HD098684"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>G protein-coupled receptors (GPCRs) facilitate the majority of signal transductions across cell membranes in humans, with numerous diseases attributed to inactivating GPCR mutations. Many of these mutations result in misfolding during nascent receptor synthesis in the endoplasmic reticulum (ER), resulting in intracellular retention and degradation. Pharmacological chaperones (PCs) are cell-permeant small molecules that can interact with misfolded receptors in the ER and stabilise\/rescue their folding to promote ER exit and trafficking to the cell membrane. The neurokinin 3 receptor (NK3R) plays a pivotal role in the hypothalamic\u2013pituitary\u2013gonadal reproductive axis. We sought to determine whether NK3R missense mutations result in a loss of cell surface receptor expression and, if so, whether a cell-permeant small molecule NK3R antagonist could be repurposed as a PC to restore function to these mutants. Quantitation of cell surface expression levels of seven mutant NK3Rs identified in hypogonadal patients indicated that five had severely impaired cell surface expression. A small molecule NK3R antagonist, M8, increased cell surface expression in four of these five and resulted in post-translational receptor processing in a manner analogous to the wild type. Importantly, there was a significant improvement in receptor activation in response to neurokinin B (NKB) for all four receptors following their rescue with M8. This demonstrates that M8 may have potential for therapeutic development in the treatment of hypogonadal patients harbouring NK3R mutations. The repurposing of existing small molecule GPCR modulators as PCs represents a novel and therapeutically viable option for the treatment of disorders attributed to mutations in GPCRs that cause intracellular retention.<\/jats:p>","DOI":"10.3390\/ijms23094587","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T05:07:22Z","timestamp":1650604042000},"page":"4587","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-1238","authenticated-orcid":false,"given":"Ross C.","family":"Anderson","sequence":"first","affiliation":[{"name":"Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharika","family":"Hanyroup","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6840-3621","authenticated-orcid":false,"given":"Yong Bhum","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Research Center, Scripps Korea Antibody Institute, Chuncheon 24341, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4671-2997","authenticated-orcid":false,"given":"Zulfiah","family":"Mohamed-Moosa","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Anatomy and Physiology, Faculty of Veterinary Sciences, University of Pretoria, Private Bag X04, Pretoria 0110, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6333-1470","authenticated-orcid":false,"given":"Iman","family":"van den Bout","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-993X","authenticated-orcid":false,"given":"Alexis C.","family":"Schwulst","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8237-0704","authenticated-orcid":false,"given":"Ursula B.","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert P.","family":"Millar","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Integrative Biomedical Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa"},{"name":"Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9JZ, UK"},{"name":"School of Medicine, Medical and Biological Sciences Building, University of St Andrews, St Andrews KY16 9TF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6050-556X","authenticated-orcid":false,"given":"Claire L.","family":"Newton","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Pretoria 0031, South Africa"},{"name":"Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9JZ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-1-59745-205-2_7","article-title":"G Protein-Coupled Receptors Disrupted in Human Genetic Disease","volume":"448","author":"Thompson","year":"2008","journal-title":"Methods Mol. 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