Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects.

Autor: Ulloa-Aguirre A; Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición SZ, Mexico City 14080, Mexico., Zariñán T; Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México and Instituto Nacional de Ciencias Médicas y Nutrición SZ, Mexico City 14080, Mexico., Jardón-Valadez E; Departamento de Recursos de la Tierra, Universidad Autónoma Metropolitana-Lerma, Lerma de Villada 52005, Estado de México, Mexico.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Nov 15; Vol. 22 (22). Date of Electronic Publication: 2021 Nov 15.
DOI: 10.3390/ijms222212329
Abstrakt: Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.
Databáze: MEDLINE
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