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

Alfredo Ulloa-Aguirre,Teresa Zariñán,Eduardo Jardón-Valadez

doi:10.3390/ijms222212329

Abstract

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.

Highlights

Proteins are macromolecule components that play key roles in the structure, function, and regulation of all living cells
This review focuses on protein misfolding and misrouting of G protein-coupled receptors (GPCRs) involved in endocrine function
We have briefly discussed how mutations in GPCRs involved in endocrine function may affect misfolding and targeting of newly synthesized receptor proteins to the cell surface plasma membrane

Summary

Introduction

Proteins are macromolecule components that play key roles in the structure, function, and regulation of all living cells. Mutation-provoked misfolding of GPCRs involved in the regulation of reproductive function may occur [10,42], and lead to distinct abnormalities, including hypogonadotropic hypogonadism [due to mutations in the human gonadotropin-releasing hormone receptor [43], neurokinin-3 receptor (NK3R), prokineticin receptor-2 (PROKR2), or kisspeptin receptor-1 (KISS1R) [44,45,46], male pseudohermaphroditism (due to mutations in the luteinizing hormone/chorionic gonadotropin receptor; LHCGR), and ovarian failure (mutations in the follicle-stimulating hormone receptor; FSHR) [42] In these receptors misfolding leads to ER retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the PM, resulting in the inability of the receptor to interact with agonists and to trigger intracellular signaling [1,47]. Because of our long-standing experience on the human GnRHR (hGnRHR) and the gonadotropin receptors, we will focus the following discussion mainly on how mutations in these GPCRs may lead to misfolding and reproductive failure

Misfolded GnRHRs and Hypogonadotropic Hypogonadism

Chemical Approaches

Pharmacological Approaches

Findings

Conclusions