Biased Signaling and Allosteric Modulation at the FSHR

Abstract

Knowledge on G protein-coupled receptor (GPCRs) structure and mechanism of activation has profoundly evolved over the past years. The way drugs targeting this family of receptors are discovered and used has also changed. Ligands appear to bind a growing number of GPCRs in a competitive or allosteric manner to elicit balanced signaling or biased signaling (i.e., differential efficacy in activating or inhibiting selective signaling pathway(s) compared to the reference ligand). These novel concepts and developments transform our understanding of the follicle-stimulating hormone (FSH) receptor (FSHR) biology and the way it could be pharmacologically modulated in the future. The FSHR is expressed in somatic cells of the gonads and plays a major role in reproduction. When compared to classical GPCRs, the FSHR exhibits intrinsic peculiarities, such as a very large NH2-terminal extracellular domain that binds a naturally heterogeneous, large heterodimeric glycoprotein, namely FSH. Once activated, the FSHR couples to Gαs and, in some instances, to other Gα subunits. G protein-coupled receptor kinases and β-arrestins are also recruited to this receptor and account for its desensitization, trafficking, and intracellular signaling. Different classes of pharmacological tools capable of biasing FSHR signaling have been reported and open promising prospects both in basic research and for therapeutic applications. Here we provide an updated review of the most salient peculiarities of FSHR signaling and its selective modulation.

Discovery and Preclinical Development of Orally Active Small Molecules that Exhibit Highly Selective Follicle Stimulating Hormone Receptor Agonism

“…There are receptor internalization and receptor trafficking mechanisms that could be evaluated to further characterize this unique response observed among PCOS patients, and some of these are under investigation with other allosteric agonists. For example, thiazolidinone and benzamide allosteric modulators of the FSHR recruit β-arrestin to FSHR at levels 2-fold higher than rh-FSH ( De Pascali et al, 2019 ; Landomiel et al, 2019 ). A consequence of greater β-arrestin recruitment by benzamides included an increased level of ERK phosphorylation.…”

From cell surface to signalling and back: the life of the mammalian FSH receptor

“…Apart from the biased signaling at FSHR owing to mutations or SNPs (receptor bias), ligand bias has also been exhibited by glycosylation variants of FSH, antibodies acting at FSH or FSHR or by small molecule allosteric modulators of FSHR (reviewed by Landomiel 2019) [141 ]. Out of these, the small molecules can be divided in four classes based on their mode of action into allosteric agonists, positive allosteric modulators (PAMs), negative allosteric modulators (NAMs) and neutral allosteric ligands (NALs) [142 ].…”

The Low-Molecular-Weight Ligands of the Gonadotropin Receptors as the New Generation of the Regulators of the Reproductive Functions and Steroidogenesis

“…By activating G q/11 proteins, the gonadotropins stimulate the phosphoinositide-specific phospholipase Cβ (PLCβ), which catalyzes the formation of inositol-3,4,5-triphosphate and diacylglycerol, the important second messengers. This induces the activation of calcium-dependent signaling and different isoforms of protein kinase C [15][16][17][18][19]. A specific interaction between the β-arrestins and the GPCR kinases-phosphorylated sites located within the intracellular loops of the LH and FSH receptors induces G Figure 1.…”

“…protein-independent stimulation of the MAPK cascade and is involved in the internalization, endocytosis, and recyclization of the gonadotropin receptor complexes [18][19][20][21][22]. The Ca 2+ -and β-arrestin-dependent pathways, as well as the AC signaling system, are involved in the regulation of the synthesis and secretion of sex steroid hormones and also control the growth, differentiation, and survival of the testicular and ovarian cells (Figure 1).…”

“…), and their ability to form the dimeric and oligomeric complexes, as well as (iii) the functional activity of the downstream regulatory and accessory proteins (the G proteins, β-arrestins, etc.) [6,19,24,25]. A specific binding of gonadotropin to ectodomain generates a large set of the active conformations of receptor, which triggers some intracellular pathways at once and, as a result, induces multiple cell responses.…”