Allosteric Regulation of the Follicle-Stimulating Hormone Receptor

Abstract

Follicle-stimulating hormone receptor (FSHR) belongs to the leucine-rich repeat family of the G protein-coupled receptor (LGR), which includes the glycoprotein hormone receptors luteinizing hormone receptor, thyrotropin receptor, and other LGRs 4, 5, 6, and 7. FSH is the key regulator of folliculogenesis in females and spermatogenesis in males. FSH elicits its physiological response through its cognate receptor on the cell surface. Binding of the hormone FSH to its receptor FSHR brings about conformational changes in the receptor that are transduced through the transmembrane domain to the intracellular region, where the downstream effector interaction takes place, leading to activation of the downstream signaling cascade. Identification of small molecules that could activate or antagonize FSHR provided interesting tools to study the signal transduction mechanism of the receptor. However, because of the nature of the ligand-receptor interaction of FSH-FSHR, which contains multiple sites in the extracellular binding domain, most of the small-molecule modulators of FSHR are unable to bind to the orthosteric site of the receptors. Rather they modulate receptor activation through allosteric sites in the transmembrane region. This review will discuss allosteric modulation of FSHR primarily through the discovery of small-molecule modulators, focusing on current data on the status of development and the utility of these as tools to better understand signaling mechanisms.

Intervention Strategies into Glycoprotein Hormone Receptors for Modulating (Mal–)function, with Special Emphasis on the TSH Receptor

“…Correlating to the canonical orthosteric ligand binding pocket between the seven transmembrane helices of many GPCR, there is also a binding pocket in the GPHR, for which no natural ligand is known. That is where small molecules can bind allosterically into it and also modulate the 7TMH bundle of GPHR to either an active [30] or inactive [31] conformation (▶Fig. 1).…”

“…In case of malfunction, positive allosteric modulators can shift the TMD into an active conformation [30]. In case of pathologic activation, negative allosteric modulators can freeze the TMD in an inactive [31] conformation. viewed in [31]).…”

“…In case of pathologic activation, negative allosteric modulators can freeze the TMD in an inactive [31] conformation. viewed in [31]). Moreover, from homologous TSHR trimer models with bound antibodies the authors concluded that stimulating antibody M22 unlike blocking antibody K1-70 [48,51,64] causes steric hindrances in a TSHR-trimer and thus dissociates it as well.…”

“…FSH is most important among the clinical therapeutics for treatment of infertility, and is used primarily for women to induce controlled ovarian stimulation, while certain populations of infertile men also benefit from FSH treatment. A number of activating and inactivating mutations, single nucleotide polymorphisms, and spliced variants of the FSHR gene have been reported in selected infertile cases [31].…”

Breach of ligand-receptor interaction in pathogenesis of disadaptive disorders and in pathology

“…Эндогенный гликопротеин, фолликулостимулирующий гормон (FSH), является ключевым регулятором фолликулогенеза у самок, который воздействует через свой родственный рецептор на поверхности клетки. В результате связывания гормона с его рецептором FSHR происходят конформационные изменения рецептора, которые трансдуцируются через трансмембранный домен во внутриклеточную область, где осуществляется последующее эффекторное взаимодействие, приводящее к активации нижестоящего сигнального каскада [54].…”