Follicle-stimulating hormone (FSH) is produced in the pituitary and is essential for reproduction. It specifically binds to a membrane receptor (FSHR) expressed in somatic cells of the gonads. The FSH/FSHR system presents many peculiarities compared to classical G protein-coupled receptors (GPCRs). FSH is a large naturally heterogeneous heterodimeric glycoprotein. The FSHR is characterized by a very large NH2-terminal extracellular domain, which binds FSH and participates to the activation/inactivation switch of the receptor. Once activated, the FSHR couples to Gαs and, in some instances, to other Gα-subunits. GPCR kinases and β-arrestins are also recruited to the FSHR and account for its desensitization, the control of its trafficking and its intracellular signaling. Of note, the FSHR internalization and recycling are very fast and involve very early endosomes (EE) instead of EE. All the transduction mechanisms triggered upon FSH stimulation lead to the activation of a complex signaling network that controls gene expression by acting at multiple levels. The integration of these mechanisms not only leads to context-adapted responses from the target gonadal cells but also indirectly affects the fate of germ cells. Depending on the physiological/developmental stage, FSH elicits proliferation, differentiation, or apoptosis in order to maintain the homeostasis of the reproductive system. Pharmacological tools targeting FSHR recently came to the fore and open promising prospects both for basic research and therapeutic applications. This chapter provides an updated review of the most salient aspects and peculiarities of FSHR biology and pharmacology.
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.
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