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Hanyroup S, Anderson RC, Nataraja S, et al. Rescue of Cell Surface Expression and Signaling of Mutant Follicle-Stimulating Hormone Receptors. Endocrinology. 2021;162(12)doi: 10.1210/endocr/bqab134.
Hanyroup, S., Anderson, R. C., Nataraja, S., Yu, H. N., Millar, R. P., & Newton, C. L. (2021). Rescue of Cell Surface Expression and Signaling of Mutant Follicle-Stimulating Hormone Receptors. Endocrinology, 162(12), . https://doi.org/10.1210/endocr/bqab134
Hanyroup, Sharika, et al. "Rescue of Cell Surface Expression and Signaling of Mutant Follicle-Stimulating Hormone Receptors." Endocrinology vol. 162,12 (2021). doi: https://doi.org/10.1210/endocr/bqab134
Hanyroup S, Anderson RC, Nataraja S, Yu HN, Millar RP, Newton CL. Rescue of Cell Surface Expression and Signaling of Mutant Follicle-Stimulating Hormone Receptors. Endocrinology. 2021 Dec 01;162(12). doi: 10.1210/endocr/bqab134. PMID: 34192304.
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Endocrinology. 2021 Dec 01;162(12). doi: 10.1210/endocr/bqab134.

Rescue of Cell Surface Expression and Signaling of Mutant Follicle-Stimulating Hormone Receptors.

Endocrinology

Sharika Hanyroup, Ross C Anderson, Selvaraj Nataraja, Henry N Yu, Robert P Millar, Claire L Newton

Affiliations

  1. Centre for Neuroendocrinology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
  2. Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
  3. Department of Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
  4. Mitobridge Inc., Cambridge, MA, USA.
  5. CanWell Pharma Inc., Wellesley, MA, USA.
  6. Department of Integrative Biomedical Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
  7. Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
  8. School of Medicine, Medical and Biological Sciences Building, University of St Andrews, St Andrews, UK.

PMID: 34192304 DOI: 10.1210/endocr/bqab134

Abstract

Mutations in G protein-coupled receptors (GPCRs) underlie numerous diseases. Many cause receptor misfolding and failure to reach the cell surface. Pharmacological chaperones are cell-permeant small molecules that engage nascent mutant GPCRs in the endoplasmic reticulum, stabilizing folding and "rescuing" cell surface expression. We previously demonstrated rescue of cell surface expression of luteinizing hormone receptor mutants by an allosteric agonist. Here we demonstrate that a similar approach can be employed to rescue mutant follicle-stimulating hormone receptors (FSHRs) with poor cell surface expression using a small-molecule FSHR agonist, CAN1404. Seventeen FSHR mutations described in patients with reproductive dysfunction were expressed in HEK 293T cells, and cell surface expression was determined by enzyme-linked immunosorbent assay of epitope-tagged FSHRs before/after treatment with CAN1404. Cell surface expression was severely reduced to ≤18% of wild-type (WT) for 11, modestly reduced to 66% to 84% of WT for 4, and not reduced for 2. Of the 11 with severely reduced cell surface expression, restoration to ≥57% of WT levels was achieved for 6 by treatment with 1 µM CAN1404 for 24 h, and a corresponding increase in FSH-induced signaling was observed for 4 of these, indicating restored functionality. Therefore, CAN1404 acts as a pharmacological chaperone and can rescue cell surface expression and function of certain mutant FSHRs with severely reduced cell surface expression. These findings aid in advancing the understanding of the effects of genetic mutations on GPCR function and provide a proof of therapeutic principle for FSHR pharmacological chaperones.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Keywords: G protein-coupled receptor mutations; follicle-stimulating hormone receptors; pharmacological chaperones; reproductive dysfunction

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