Please be advised that the site will be down for maintenance on Sunday, September 1, 2024, from 08:00 to 18:00, and again on Monday, September 2, 2024, from 08:00 to 09:00. We apologize for any inconvenience this may cause.
dc.contributor.author | Radomsky, Tarryn![]() |
|
dc.contributor.author | Anderson, Ross Calley![]() |
|
dc.contributor.author | Millar, Robert P.![]() |
|
dc.contributor.author | Newton, Claire L.![]() |
|
dc.date.accessioned | 2024-08-07T06:11:14Z | |
dc.date.available | 2024-08-07T06:11:14Z | |
dc.date.issued | 2024 | |
dc.description | DATA AVAILABILITY STATEMENT : Data sharing is not applicable to this article as no new data were created or analysed in this study. | en_US |
dc.description.abstract | G protein-coupled receptors (GPCRs) are central to the functioning of the hypothalamic–pituitary–gonadal axis (HPG axis) and include the rhodopsin-like GPCR family members, neurokinin 3 receptor, kappa-opioid receptor, kisspeptin 1 receptor, gonadotropin-releasing hormone receptor, and the gonadotropin receptors, luteinizing hormone/choriogonadotropin receptor and follicle-stimulating hormone receptor. Unsurprisingly, inactivating variants of these receptors have been implicated in a spectrum of reproductive phenotypes, including failure to undergo puberty, and infertility. Clinical induction of puberty in patients harbouring such variants is possible, but restoration of fertility is not always a realisable outcome, particularly for those patients suffering from primary hypogonadism. Thus, novel pharmaceuticals and/or a fundamental change in approach to treating these patients are required. The increasing wealth of data describing the effects of coding-region genetic variants on GPCR function has highlighted that the majority appear to be dysfunctional as a result of misfolding of the encoded receptor protein, which, in turn, results in impaired receptor trafficking through the secretory pathway to the cell surface. As such, these intracellularly retained receptors may be amenable to ‘rescue’ using a pharmacological chaperone (PC)-based approach. PCs are small, cell permeant molecules hypothesised to interact with misfolded intracellularly retained proteins, stabilising their folding and promoting their trafficking through the secretory pathway. In support of the use of this approach as a viable therapeutic option, it has been observed that many rescued variant GPCRs retain at least a degree of functionality when ‘rescued’ to the cell surface. In this review, we examine the GPCR PC research landscape, focussing on the rescue of inactivating variant GPCRs with important roles in the HPG axis, and describe what is known regarding the mechanisms by which PCs restore trafficking and function. We also discuss some of the merits and obstacles associated with taking this approach forward into a clinical setting. | en_US |
dc.description.department | Immunology | en_US |
dc.description.department | Physiology | en_US |
dc.description.librarian | hj2024 | en_US |
dc.description.sdg | SDG-03:Good heatlh and well-being | en_US |
dc.description.sponsorship | The National Research Foundation, South Africa. | en_US |
dc.description.uri | http://wileyonlinelibrary.com/journal/jne | en_US |
dc.identifier.citation | Radomsky, T., Anderson, R.C., Millar, R.P. & Newton, C.L. Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic–pituitary– gonadal axis. Journal of Neuroendocrinology 2024; e13418. doi:10.1111/jne.13418. | en_US |
dc.identifier.issn | 0953-8194 (print) | |
dc.identifier.issn | 1365-2826 (online) | |
dc.identifier.other | 10.1111/jne.13418 | |
dc.identifier.uri | http://hdl.handle.net/2263/97474 | |
dc.language.iso | en | en_US |
dc.publisher | Wiley | en_US |
dc.rights | © 2024 The Author(s). Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License. | en_US |
dc.subject | G protein-coupled receptor (GPCR) | en_US |
dc.subject | Hypothalamic–pituitary–gonadal axis (HPG axis) | en_US |
dc.subject | Pharmacological chaperone | en_US |
dc.subject | Pharmacoperone | en_US |
dc.subject | Reproduction | en_US |
dc.subject | SDG-03: Good health and well-being | en_US |
dc.title | Restoring function to inactivating G protein-coupled receptor variants in the hypothalamic–pituitary–gonadal axis1 | en_US |
dc.type | Article | en_US |