Intracellular Trafficking of Gonadotropin Receptors in Health and Disease

Abstract

Gonadotropin receptors belong to the highly conserved subfamily of the G protein-coupled receptor (GPCR) superfamily, the so-called Rhodopsin-like family (class A), which is the largest class of GPCRs and currently a major drug target. Both the follicle-stimulating hormone receptor (FSHR) and the luteinizing hormone/chorionic gonadotropin hormone receptor (LHCGR) are mainly located in the gonads where they play key functions associated to essential reproductive functions. As any other protein, gonadotropin receptors must be properly folded into a mature tertiary conformation compatible with quaternary assembly and endoplasmic reticulum export to the cell surface plasma membrane. Several primary and secondary structural features, including presence of particular amino acid residues and short motifs and in addition, posttranslational modifications, regulate intracellular trafficking of gonadotropin receptors to the plasma membrane as well as internalization and recycling of the receptor back to the cell surface after activation by agonist. Inactivating mutations of gonadotropin receptors may derive from receptor misfolding and lead to absent or reduced plasma membrane expression of the altered receptor, thereby manifesting an array of phenotypical abnormalities mostly characterized by reproductive failure and/or abnormal or absence of development of secondary sex characteristics. In this chapter we review the structural requirements necessary for intracellular trafficking of the gonadotropin receptors, and describe how mutations in these receptors may lead to receptor misfolding and disease in humans.

Structure-Function Relationships of the Follicle-Stimulating Hormone Receptor

“…Similar to other GPCRs, if the FSHR is not correctly folded the quality control surveillance of the proteosome removes the misfolded receptor. If properly folded, in the ER FSHR continues its transit to the Golgi and the PM ( 46 ). N-linked glycosylation (as well as disulfide bond formation) is a frequent feature of GPCRs that occurs during biosynthesis and facilitates folding of protein precursors by increasing their solubility, protecting from detrimental non-productive protein-protein interactions and stabilizing protein conformation ( 47 ).…”

Molecular dynamics simulation of the follicle-stimulating hormone receptor. Understanding the conformational dynamics of receptor variants at positions N680 and D408 from in silico analysis

“…In the case of the M3 mutant, which leads to hypergonadotropic primary amenorrhea [20], we found that replacement of aspartate with tyrosine at this position led to disruption of the interactions between TM helix 2 and helix 7 detected in the functional variants, with Y408 showing contacts with N380 of TM helix 1, S456 at TM helix 4, C584 at TM helix 6, and H615, N618, and N622 at TM helix 7, not exhibited by the WT I1 variant. The interhelical interactions disrupted in Y408 impacted on the receptor dynamics by reducing the conformational variability at the backbone level, which could be a feature recognized by the quality control system of the cell, thereby leading to intracellular trapping of the mutant receptor [21], a situation shared by M1. Map contacts in M1 and M2 mutants also evidenced the influence of the side chain atoms at position 408: a. Alanine side chain in M1 almost lost interaction with S619 at TM helix 7; and b.…”

“…Mutations on the human FSHR have allowed identification of amino acid residues important for receptor function. For example, the loss-of-function, naturally occurring mutation D408Y found in patients with hypergonadotropic amenorrhea has been associated with intracellular trapping of the receptor probably due to misfolding and impaired upward traffic from the endoplasmic reticulum to the cell surface plasma membrane [20, 21]. Expression of the most common and best studied functional variants of the wild-type (WT) FSHR resulting from single nucleotide polymorphisms (SNP) with either alanine or threonine at position 307, and asparagine or serine at position 680 (which are expressed in strong linkage disequilibrium) also have been studied [22, 23].…”

Sleep-Wake Cycling and Energy Conservation: Role of Hypocretin and the Lateral Hypothalamus in Dynamic State-Dependent Resource Optimization

“…Historically, the anterior hypothalamus has been viewed as a “sleep center” since lesions in this area are known to cause long-lasting insomnia, whereas the posterior hypothalamus has been viewed as a “waking center” since its lesioning causes excessive sleepiness [see Saper et al ( 67 )]. Although this anterior-posterior classification of “sleep” vs. “waking” centers may be an oversimplification given the role other brain circuits ( 123 – 125 ), many of these historical insights still hold true today.…”