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

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.

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…The need to create allosteric regulators is due to both the low selectivity of LH and hCG to intracellular cascades and the peculiarities of pharmacological preparations of gonadotropins since their urinary forms (hCG) have a significant number of bioactive impurities and are variable in specific activity, while recombinant forms (LH, hCG) significantly differ from natural gonadotropins in the pattern of N-glycosylation and regulatory properties. Along with this, gonadotropins are not very effective in the case of mutant forms of LHR, which have a reduced ligand-binding capacity or impaired translocation to the membrane, even if binding to gonadotropin is preserved [ 382 , 383 , 384 ]. In this regard, it should be noted that some of the developed small allosteric LHR agonists have the properties of chaperones, which stabilize the structure of LHR and facilitate their translocation to the plasma membrane, which increases their sensitivity to endogenous LH, as was experimentally shown for thieno[2,3-d]-pyrimidine derivative Org42599 [ 385 , 386 , 387 ].…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…The need to create allosteric regulators is due to both the low selectivity of LH and hCG in relation to intracellular cascades, and the peculiarities of pharmacological preparations of gonadotropins, since their urinary forms (hCG) have a significant number of bioactive impurities and are variable in specific activity, while recombinant forms (LH, hCG) significantly differ from natural gonadotropins in the pattern of N-glycosylation and regulatory properties. Along with this, gonadotropins are not very effective in the case of mutant forms of LHR, which have a reduced ligand-binding ability or impaired translocation to the membrane, even when binding to gonadotropin is preserved [382][383][384]. In this regard, it should be noted that some of the developed small allosteric LHR agonists have the properties of chaperones, which stabilize the structure of LHR and facilitate their translocation to the plasma membrane, which increases their sensitivity to endogenous LH, as was experimentally shown for thieno [2,3-d]-pyrimidine derivative Org42599 [385][386][387].…”

Genetic variants of G‐protein coupled receptors associated with pubertal disorders

“… 1 , 2 , 3 GPCRs consist of an extracellular N‐terminus, seven transmembrane domains connected by intracellular and extracellular loops, and an intracellular C‐terminus. 1 , 2 More than 800 GPCRs are encoded in the human genome. 4 , 5 Natural ligands of GPCRs include small peptides, lipids, ions, odorants, and large glycoproteins.…”