Glycoprotein G-protein Coupled Receptors in Disease: Luteinizing Hormone Receptors and Follicle Stimulating Hormone Receptors

Abstract

Signal transduction by luteinizing hormone receptors (LHRs) and follicle-stimulating hormone receptors (FSHRs) is essential for the successful reproduction of human beings. Both receptors and the thyroid-stimulating hormone receptor are members of a subset of G-protein coupled receptors (GPCRs) described as the glycoprotein hormone receptors. Their ligands, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and a structurally related hormone produced in pregnancy, human chorionic gonadotropin (hCG), are large protein hormones that are extensively glycosylated. Although the primary physiologic functions of these receptors are in ovarian function and maintenance of pregnancy in human females and spermatogenesis in males, there are reports of LHRs or FSHRs involvement in disease processes both in the reproductive system and elsewhere. In this review, we evaluate the aggregation state of the structure of actively signaling LHRs or FSHRs, their functions in reproduction as well as summarizing disease processes related to receptor mutations affecting receptor function or expression in reproductive and non-reproductive tissues. We will also present novel strategies for either increasing or reducing the activity of LHRs signaling. Such approaches to modify signaling by glycoprotein receptors may prove advantageous in treating diseases relating to LHRs or FSHRs function in addition to furthering the identification of new strategies for modulating GPCR signaling.

Keywords: follicle-stimulating hormone receptor; hormones; luteinizing hormone receptor.

Figure 1

Structure of luteinizing hormone receptors (LHRs) showing the hormone-binding domain, the hinge region and the hinge loop, the seven transmembrane domains, and the intracellular C terminus. Mutations to amino acids shaded in red lead to LHRs loss of function.

Figure 2

Structure of the follicle-stimulating hormone receptors (FSHRs) showing the hormone-binding domain, hinge region, seven transmembrane segments, and the intracellular C terminus. Mutations to amino acids shaded in red lead to the FSHRs loss of function [21]. This figure was reprinted from [21] under the terms of the Creative Commons Attribution 4.0 License.

Figure 3

Structures of follicle-stimulating hormone (FSH) (A), and luteinizing hormone (LH) (B), and human chorionic gonadotropin (hCG) (C) showing the α and β subunits of each hormone. When compared to human LHRs (hLHs), the β subunit of hCG has additional amino acids and extensive glycosylation on the C-terminal tail that contribute to its higher molecular weight. FSH and hCG structures were from reprinted from [24] with permission from Elsevier. The figure of hLHs shown in the middle panel was provided by Dr. George Bousfield.

Figure 4

Schematic representation of cis-activation (A) and trans-activation (B) of a glycoprotein hormone receptor. Cis-activation occurs when hormone bound to the LHRs or FSHRs extracellular domain interacts with the portions of the same receptor involved in signal transduction. Trans-activation occurs when the hormone bound to the extracellular domain on one receptor interacts with an adjoining receptor that then initiates signal transduction. This figure was reprinted from [59] under the terms of the Creative Commons Attribution 4.0 License.

Figure 5

Comparison of the extent of LHR aggregation in cells expressing physiologically relevant receptor numbers (32 k LHR/cell) and cells overexpressing LHRs (122 k LHR/cell). The extent of receptor aggregation was measured as a function of receptor anisotropy (Y-axis, left). Decreased anisotropy values indicate more extensive clustering of the receptor, as shown by the arrow. The extent of receptor clustering was compared to intracellular cAMP levels (Y-axis, right) measured using a cAMP probe. In some experiments, cells were pre-treated with decavanadate (V10), which reduced the extent of membrane lipid packing (data not shown) while causing increased clustering of LHRs and increased cAMP [125]. Pre-treatment of cells with 100 nM deglycosylated hCG (DG), reduced receptor clustering, and reduced cAMP signaling. Both homo-FRET results and intracellular cAMP levels are expressed as mean ±SEM of 30 measurements for each condition. Statistical evaluation of mean differences in untreated and treatment groups was analyzed by one-way ANOVA followed by the Tukey multiple comparison test and Student’s t-test to compare between two groups using R version 3.3.1. p-values < 0.05 were statistically significant.