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Endocrine Abstracts (2022) 86 S4.1 | DOI: 10.1530/endoabs.86.S4.1

1University of Pretoria, Pretoria, South Africa. 2Mitobridge Inc, Cambridge, USA. 3CanWell Pharma Inc, Wellesley, USA. 4Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. 5University of Cape Town, Cape Town, South Africa

G protein-coupled receptors (GPCRs) are critical for signal transduction within neuroendocrine signalling pathways, and genetic mutations in G protein-coupled GPCRs underlie numerous diseases. Inactivating GPCR mutations can impede ligand interactions or signal transduction, or can result in misfolding of nascent receptor proteins and subsequent retention in the endoplasmic reticulum (ER) and thus failure to traffic to the cell surface. Examination of the functionality and cell surface expression of a number of mutations of the gonadotrophin hormone receptors (luteinising hormone receptor and follicle-stimulating hormone receptor) have revealed that the majority of mutations in these receptors result in severely reduced cell surface expression. Pharmacological chaperones (PCs) are cell-permeant small-molecules that engage misfolded proteins in the ER, stabilising their folding and ‘rescuing’ cell surface expression. The ability of existing small-molecule ligands to act as PCs for gonadotrophin receptor mutants with poor cell surface expression revealed that they can exhibit PC activity. Importantly, following treatment with the PC compounds, in addition to an increase in cell surface expression of the mutant receptors, a corresponding increase in hormone-induced signalling was observed for many of the ‘rescued’ receptors, indicating restored functionality. Furthermore, some of the test ligands that interact with their target receptors at allosteric sites distinct from the natural ligand (allo-agonists), were able to elicit a robust response from mutant receptors with normal cell surface expression, but impaired hormone/binding/signalling. These findings aid in advancing understanding of the effects of genetic mutations on GPCR function, and the actions of small molecule ligands on such, and provide a proof of therapeutic principle for neuroendocrine PCs/allosteric agonists.

Volume 86

Society for Endocrinology BES 2022

Harrogate, United Kingdom
14 Nov 2022 - 16 Nov 2022

Society for Endocrinology 

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