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Like other proteins, G protein\u2010coupled receptors need to be properly folded in order to traffic to the plasma membrane and interact with agonist.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Herein, we briefly review the process of folding and intracellular traffic of G protein\u2010coupled receptors, with a focus on the gonadotropin\u2010releasing hormone receptor and the gonadotropin receptors, whose variants can lead to misfolding, loss of plasma membrane trafficking and eventually to different forms of hypogonadism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and Discussion<\/jats:title>\n                    <jats:p>Pathogenic variants of G protein\u2010coupled receptors may provoke loss\u2010of\u2010function of the receptor protein, thereby leading to disease. The presence of a stringent cellular quality control system promotes proper protein folding compatible with endoplasmic reticulum export and concomitantly prevents unfolded proteins accumulating within the cell. Molecular chaperones and companion factors are key elements of the quality control system that maintain the integrity of the proteostasis network by regulating, at different levels folding and assembly of nascent proteins and by promoting degradation of defective conformers, preventing aggregation and toxic accumulation. Due to the importance of the concept of molecular chaperoning in protein folding, pharmacoperone drugs emulating the role of endogenous chaperones as stabilizers of protein conformation currently represent a novel therapeutic opportunity for rescuing misfolded receptors and treating different diseases due to protein misfolding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In vitro and in vivo studies in experimental animals and in humans have provided proof\u2010of\u2010principle of the beneficial effects of pharmacoperone drugs in modifying the course of human disease due to misfolding of G protein\u2010coupled receptors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/andr.70018","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T19:57:45Z","timestamp":1741723065000},"page":"978-991","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Folding, misfolding, and regulation of intracellular traffic of G protein\u2010coupled receptors involved in the hypothalamic\u2013pituitary\u2013gonadal axis"],"prefix":"10.1111","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-3886","authenticated-orcid":false,"given":"Alfredo","family":"Ulloa\u2010Aguirre","sequence":"first","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Mexico City Mexico"},{"name":"Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n Mexico City Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ross C.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences University of Pretoria Gezina Pretoria South Africa"},{"name":"Department of Physiology, Faculty of Health Sciences University of Pretoria Gezina Pretoria South Africa"}],"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 (UNAM) Mexico City Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rub\u00e9n","family":"Guti\u00e9rrez\u2010Sagal","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM) Mexico City Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Jard\u00f3n\u2010Valadez","sequence":"additional","affiliation":[{"name":"Departamento de Recursos de la Tierra Unidad Lerma, Universidad Auto\u00b4noma Metropolitana, Lerma de Villada, Estado de M\u00e9xico Mexico City Mexico"}],"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, Department of Immunology, Faculty of Health Sciences University of Pretoria Gezina Pretoria South Africa"},{"name":"Deanery of Biomedical Sciences, University of Edinburgh Edinburgh UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2004\u20100010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1591"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.73.011303.073752"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2016"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5282.1725"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2468"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/35008096"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02261"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2003.12.008"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2004.00232.x"},{"key":"e_1_2_9_12_1","first-page":"87","volume-title":"Handbook of Physiology. 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