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Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones

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), res...

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Autores principales: Anderson, Ross C., Hanyroup, Sharika, Song, Yong Bhum, Mohamed-Moosa, Zulfiah, van den Bout, Iman, Schwulst, Alexis C., Kaiser, Ursula B., Millar, Robert P., Newton, Claire L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100388/
https://www.ncbi.nlm.nih.gov/pubmed/35562976
http://dx.doi.org/10.3390/ijms23094587
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author Anderson, Ross C.
Hanyroup, Sharika
Song, Yong Bhum
Mohamed-Moosa, Zulfiah
van den Bout, Iman
Schwulst, Alexis C.
Kaiser, Ursula B.
Millar, Robert P.
Newton, Claire L.
author_facet Anderson, Ross C.
Hanyroup, Sharika
Song, Yong Bhum
Mohamed-Moosa, Zulfiah
van den Bout, Iman
Schwulst, Alexis C.
Kaiser, Ursula B.
Millar, Robert P.
Newton, Claire L.
author_sort Anderson, Ross C.
collection PubMed
description 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–pituitary–gonadal 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.
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spelling pubmed-91003882022-05-14 Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones Anderson, Ross C. Hanyroup, Sharika Song, Yong Bhum Mohamed-Moosa, Zulfiah van den Bout, Iman Schwulst, Alexis C. Kaiser, Ursula B. Millar, Robert P. Newton, Claire L. Int J Mol Sci Article 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–pituitary–gonadal 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. MDPI 2022-04-21 /pmc/articles/PMC9100388/ /pubmed/35562976 http://dx.doi.org/10.3390/ijms23094587 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Anderson, Ross C.
Hanyroup, Sharika
Song, Yong Bhum
Mohamed-Moosa, Zulfiah
van den Bout, Iman
Schwulst, Alexis C.
Kaiser, Ursula B.
Millar, Robert P.
Newton, Claire L.
Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones
title Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones
title_full Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones
title_fullStr Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones
title_full_unstemmed Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones
title_short Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones
title_sort functional rescue of inactivating mutations of the human neurokinin 3 receptor using pharmacological chaperones
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100388/
https://www.ncbi.nlm.nih.gov/pubmed/35562976
http://dx.doi.org/10.3390/ijms23094587
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