Chapter One - Follicle-Stimulating Hormone Receptor: Advances and Remaining Challenges
Introduction
Follicle-stimulating hormone (FSH) plays a crucial role in the control of male and female reproduction. FSH is a heterodimeric glycoprotein consisting of an α-subunit, common with the other glycoprotein hormones (i.e., luteinizing hormone—LH, chorionic gonadotropin—CG, and thyroid-stimulating hormone—TSH), which is noncovalently associated with a specific FSHβ-subunit (Pierce and Parsons, 1981; Ryan et al., 1987). FSH is synthesized and secreted by the pituitary. FSH binds to and activates a plasma membrane receptor (FSHR) that belongs to the rhodopsin family of the G protein-coupled receptor (GPCR) superfamily. The FSHR displays a high degree of tissue specificity, being expressed in Sertoli and granulosa cells located in the male and female gonads, respectively (Simoni et al., 1997) (Fig. 1). As the other glycoprotein hormone receptors, the FSHR is characterized by a large NH2-terminal extracellular domain (ECD), where FSH binds specifically.
FSH is required for normal growth and maturation of ovarian follicles in women and for normal spermatogenesis in men (Themmen and Huhtaniemi, 2000). Female mice with FSHβ or FSHR gene knockout are infertile because of an incomplete follicle development, whereas male display oligozoospermia and subfertility (Dierich et al., 1998; Kumar et al., 1997). Consistently, women expressing nonfunctional variants of the FSHR are infertile while men are oligozoospermic, yet fertile (Aittomäki et al., 1995).
Because of its glycosylation, FSH is naturally heterogeneous and must be expressed by mammalian cells (i.e., pituitary or CHO cells) to be fully active in vivo. Because of these characteristics, only native forms of FSH, either purified from urine or recombinant, are being used in reproductive medicine, no other pharmacological agents being currently available in clinic (Lunenfeld, 2004; Macklon et al., 2006). Some women treated with FSH develop an ovarian hyperstimulation syndrome (OHSS), which, in its severe forms, can be life threatening (Vloeberghs et al., 2009). Therefore, pharmacological agents that would induce ovulation without the risk of provoking OHSS would represent a major improvement. It is also well established that, in women, the responsiveness to FSH treatment is heterogeneous and that the dose and sometimes the source of FSH, have to be empirically adjusted for each patient (Loutradis et al., 2003, Loutradis et al., 2004). A larger panel of FSHR agonists with varying pharmacological profiles could certainly help improving the overall efficiency of medically assisted procreation. On the other hand, FSHR blockers could potentially represent a novel nonsteroidal approach for contraception (Naz et al., 2005).
In order to meet these challenges, it is important to gain a better understanding of FSHR biology and the bottlenecks that make the targeting of this receptor particularly difficult.
Section snippets
FSH and FSHR in Pathologies
FSH serum levels vary physiologically during the menstrual cycle in women. Nevertheless, abnormal pituitary FSH secretion can occur in different pathologies such as premature ovarian insufficiency (POI) and polycystic ovarian syndrome (PCOS). POI is a dysfunction of the ovary occurring in about 1% of female population (under 40 years old) (Goswami and Conway, 2005). Patients carrying POI are infertile due to anovulation, amenorrhea, and reduced secretion of oestrogens (Kalantaridou et al., 1998
FSH Role in Assisted Reproduction Technologies (ARTs)
Assisted reproduction techniques (ARTs) are defined as “all treatments or procedures that include the in vitro handling of both human oocytes and sperm or embryos for the purpose of establishing a pregnancy” (Zegers-Hochschild et al., 2009). The procedures involved in ART include in vitro fertilization (IVF), gamete intrafalloppian transfer, and intracytoplasmic sperm injection. Although a universal ART protocol does not exist, the main steps are common to each technique (Casarini et al., 2016a
FSHR Structure and Function
The human FSHR, together with LHR and TSHR, belongs to the glycoprotein hormone receptors subfamily of class A GPCRs. It is encoded by a unique gene constituted of 10 exons and located on chromosome 2p21-p16 (Rousseau-Merck et al., 1993). After releasing of a signal peptide of 17 amino acids, the mature membrane FSHR protein contains 678 amino acids. Its molecular weight varies between 82 and 89 kDa depending on the rate of N-glycosylation (Davis et al., 1995). Several splice variants have been
FSHR Mutations
Although rare in the population, activating and inactivating mutations of FSHR have been reported in both genders (Desai et al., 2013; Riccetti et al., 2017; Ulloa-Aguirre et al., 2014). Both types of mutations can cause alteration of reproductive function, even though the phenotype is often more severe for woman fertility. In most cases, inactivating mutations provoke primary or secondary amenorrhea whereas the activating ones generally lead to OHSS. Some studies described the impact of
FSHR Signaling Through G Proteins
Unlike many GPCRs, in the absence of ligand, the FSHR displays little to no constitutive activity (Ulloa-Aguirre et al., 2014). This functional characteristic correlates with the increased stability of the transmembrane domains in the inactive state compared to other glycoprotein hormone receptors (Ulloa-Aguirre et al., 2014; Zhang et al., 2007). Upon FSH binding, conformational changes in the receptor lead to the transduction of the extracellular signal, hence the activation of several
FSHR Desensitization, Internalization, and Recycling
The FSHR is regulated by the canonical desensitization mechanisms known to operate for most GPCR (Fig. 3). Briefly, agonist-activated FSHR is rapidly phosphorylated on serine/threonine residues located on its carboxyl terminus through the action of GPCR kinases (GRKs), specifically GRKs 2, 3, 5, and 6 (Ayoub et al., 2015; Kara et al., 2006; Lazari et al., 1999; Marion et al., 2006; Moore et al., 2007; Troispoux et al., 1999; Ulloa-Aguirre and Zarinan, 2016). Nonvisual arrestins (β-arrestin 1
FSHR Signaling Through β-Arrestin
Beyond their well-established role in receptor desensitization, internalization, and recycling, β-arrestins have progressively emerged as key players in the control of GPCR-mediated signals in time and space (Fig. 3). Many GPCRs, including FSHR, have been demonstrated to signal independently of heterotrimeric G protein, through ligand-induced β-arrestin 1 and 2 recruitment (Reiter et al., 2012, Reiter et al., 2017; Reiter and Lefkowitz, 2006). Indeed, β-arrestins act as multifunctional
Modeling of FSHR Signaling
FSH signaling acts at different timescales within the hypothalamic–pituitary–gonadal (HPG) axis, encoding and decoding complex signals across several organs and tissues from the pituitary cells to the somatic cells in the gonads. Capturing the mechanisms responsible for such refined controls has proven very challenging. Over the years, this topic has led to the development of numerous mathematical models.
Fluctuations of FSH circulating levels are tightly regulated with respect to those of LH,
Impact on Gene Regulation
FSH directly alters the pattern of genes expressed in somatic cells of the gonads by regulating transcriptional as well as posttranscriptional events at the level of mRNA translation and of the miRNA network. The FSH-induced signaling network also indirectly promotes alterations of chromatin condensation in germ cells. Gaining a comprehensive picture on the FSH-regulated gene expression could provide insights on how gonadal somatic cells communicate with their neighboring germ cells. This could
Impact on Proliferation/Apoptosis/Cell Survival
FSH is an important contributor to the fate of somatic cells of the male and female gonad. Respectively, in Sertoli cells and granulosa cells, the hormone regulates proliferation and commitment to differentiation. In addition, in the ovary, FSH protects granulosa cells from atresia, a degenerative process that leads to the selection of a dominant follicle within a developing cohort. This is the main difference with the role of FSH in Sertoli cells, where apoptosis is negligible. The other
Biased Signaling
It is now well established that GPCRs adopt multiple inactive and active conformations that are connected to distinct transduction mechanisms. The notion of signaling bias is coming from this complexity. Indeed, a given ligand or receptor mutation can modify the stabilized conformation of the receptor–ligand complex, as compared to the wild-type receptor–reference–ligand complex (Galandrin et al., 2007; Granier et al., 2007; Kahsai et al., 2011; Kenakin, 2005; Kobilka, 2011; Nygaard et al., 2013
Conclusions
Many advances have been achieved over the last few years in FSHR research that open intriguing prospects in terms of pharmacological control of this receptor with potential applications in ART and contraception. Now that the proof of concept has been achieved that biased signaling exists for FSHR, the different classes of small-molecule ligands identified for the FSHR will have to be further characterized with respect to their pharmacological profiles. Are they balanced or biased? The same goes
Acknowledgments
This work was funded by “ARD 2020 Biomédicament” grants from Région Centre and with the support from the French National Research Agency under the program “Investissements d’avenir” Grant Agreement LabEx MabImprove: ANR-10-LABX-53. F.D.P. and A.T. are recipients of a Doctoral fellowship from INRA and Région Centre.
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2023, Vitamins and HormonesCitation Excerpt :These variants are due to single-nucleotide polymorphisms (SNPs) commonly detected among human populations, resulting in the modulation of FSHR-dependent intracellular signaling cascades (Casarini et al., 2014; Desai et al., 2011) and possibly impacting the ovarian response to the hormone (Borgbo et al., 2017; Conforti et al., 2022; Desai et al., 2013; Perez Mayorga et al., 2000; Simoni & Casarini, 2014). The complexity of FSHR intracellular signaling network was extensively described previously (Fig. 2) (Casarini & Crépieux, 2019; de Pascali et al., 2018; Gloaguen, Crépieux, Heitzler, Poupon, & Reiter, 2011; Sposini et al., 2020; Ulloa-Aguirre, Reiter, & Crepieux, 2018). Some of these signaling cascades are common to those of other glycoprotein receptors, suggesting a certain degree of conservation of the structure-function relationship across evolution (Casarini & Crépieux, 2019; Casarini, Santi, Brigante, & Simoni, 2018; Kleinau, Neumann, Grüters, Krude, & Biebermann, 2013).
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2023, Cellular SignallingCitation Excerpt :In particular, the mechanism of gonadotropin actions mediated through their respective receptors has been extensively investigated with the view that FSH and LH function as primary messengers to activate signaling pathways associated with ovarian functions. The results of these studies have revealed that, in all vertebrates studied to date, an increase in intracellular cAMP concentration is induced in follicle cells of growing or preovulatory follicles following the surge of gonadotropins [4,10–12], and that its cAMP increase leads to the activation of various signaling pathways. Studies on the role of gonadotropins in the ovaries have been intensively conducted in various mammalian species.
BMP15 regulates FSHR through TGF-β receptor II and SMAD4 signaling in prepubertal ovary of Rongchang pigs
2022, Research in Veterinary ScienceCitation Excerpt :In a word, the TGFβR and SMAD family plays a very important role in the process of TGF-β signal transduction (Du et al., 2018; Qin et al., 2019; Tzavlaki and Moustakas, 2020). As a biological macromolecule, follicle-stimulating hormone (FSH) does not penetrate the cell membrane, but mainly binds to the specific FSH receptor (FSHR) on the membrane surface of the target GCs and Sertoli cells (De Pascali et al., 2018; Devillers et al., 2019; Zhao, 2017). Interestingly, the proliferation and differentiation of GCs as well as the secretion of GC follicular fluid which induce the production of aromatase and stimulate the synthesis and secretion of estradiol regulate the development, maturation, and release of oocytes (Devillers et al., 2019; Zhao, 2017).
The Follicle-Stimulating Hormone Signaling Network in Gonadal Cells
2021, Cellular Endocrinology in Health and Disease, Second Edition