FSHR

Fig1. A simplified overview of the FSHR signaling network. (Alfredo Ulloa-Aguirre, 2018)

What is FSHR protein?

FSHR (follicle stimulating hormone receptor) gene is a protein coding gene which situated on the short arm of chromosome 2 at locus 2p16. FSHR is a membrane-bound receptor belonging to the G protein-coupled receptor (GPCR) superfamily. In humans, FSHR is mainly expressed in gonads, such as testicles and ovaries, and some non-gonadal tissues, including brain, liver, kidney, heart, and fat cells. The main physiological function of FSHR is to bind to follicle-stimulating hormone (FSH), a glycoprotein hormone secreted by the anterior pituitary gland that is essential for the development and function of the reproductive system. The FSHR protein is consisted of 695 amino acids and its molecular mass is approximately 78.3 kDa.

What is the function of FSHR protein?

The FSHR protein structure includes a large N-terminal extracellular region (ECD), a transmembrane region (TMD), and an intracellular region (ICD). The activation of FSHR can promote the growth and maturation of germ cells in the gonads, as well as the synthesis and secretion of sex hormones. In women, FSHR acts by regulating the maturation and ovulation process of the follicle, while in men, it is involved in regulating sperm production. In addition to its role in the reproductive system, FSHR's function in other tissues is also of interest, including potential roles in bone metabolism, lipid metabolism, and cognitive function.

FSHR Related Signaling Pathway

After FSHR activation, it binds to Gs protein and stimulates adenylate cyclase to produce cAMP, thereby activating protein kinase A(PKA). This signaling pathway plays a key role in follicle development, ovulation and luteal formation. FSHR activation can induce phosphorylation of the extracellular signal-regulated kinase (ERK), which in turn activates the mitogen-activated protein kinase (MAPK) signaling pathway. FSHR activation also activates the PI3K(phosphatidylinositol 3-kinase)/Akt signaling pathway by binding to Gi protein, inhibiting adenylate acylase activity and reducing cAMP level. Activation of FSHR can induce nitric oxide synthase (NOS) to produce nitric oxide (NO), and then activate guanylate cyclase to produce cGMP.

FSHR Related Diseases

FSHR is associated with a variety of diseases, particularly those related to the reproductive and metabolic systems. FSHR, a glycoprotein with an extracellular domain (ECD), a transmembrane domain (TMD), and an intracellular domain (ICD), plays a pivotal role in human metabolic diseases and cancer. It is not only involved in the reproductive process by binding to FSH, which is secreted by the pituitary gland and essential for the development and maturation of ovarian follicles and spermatogenesis in males, but also linked to the regulation of bone formation, fat metabolism, energy homeostasis, and cholesterol production. Elevated FSH levels have been associated with an increased risk of age-related diseases such as osteoporosis, obesity, dyslipidemia, and cardiovascular diseases. Additionally, FSHR polymorphisms can influence the receptor's function and are linked to conditions like polycystic ovary syndrome (PCOS), which can disrupt endocrine hormones and lead to bone loss and increased risk of fractures.

Bioapplications of FSHR

In reproductive medicine, FSHR is targeted for the treatment of infertility and other reproductive disorders. Understanding the function of FSHR and its interaction with FSH is crucial for developing drugs that can modulate its activity, thereby influencing follicle development and ovulation. In addition, agonists and antagonists of FSHR are being studied and developed to improve reproductive health and treat related diseases.

Case Study 1: Ge Zhou, 2019

Many infertile women suffered from poor ovarian response, and increased reactive oxygen species with age might mediate the poor ovarian response to FSH. In this study, the researchers collected follicular fluids and isolated granulosa cells from female patients. Increased levels of peroxynitrite, tyrosine nitrations of FSH receptor (FSHR) and apoptosis were obviously detectable with decreased FSHR protein expressions in granulosa cells of the poor ovarian responders. In KGN (a human ovarian granulosa cell line) cells, exogenous peroxynitrite could sequester FSHR in the cytoplasm, and these dislocated FSHR might suffer from proteasome-mediated degradations. Here, four peroxynitrite-mediated nitrated tyrosine residues of FSHR were identified. Site-directed mutagenesis of FSHR revealed that Y626 was pivotal for intracellular trafficking of FSHR to the cell surface. Akt-induced inactivation of FoxO3a was required for the repression of FSH on granulosa cell apoptosis.

Fig1. Identification of tyrosine nitrated FSHR protein in human GCs.

Fig2. Identification of tyrosine nitrated sites in FSHR protein.

Case Study 2: Feimei Kuang, 2020

Previously we reported that follicle stimulating hormone (FSH) affects bone degradation in human cells and in follicle stimulating hormone receptor (FSH-R) null mice. Here the researchers describe a FSH-R knockout bone-formation phenotype. They used mesenchymal stem cells (MSCs), osteoblast precursors that express FSH-R, to determine whether FSH regulates bone formation. FSH stimulates MSC cell adhesion 1-3 h and proliferation at 24 h after addition. On the basis of phylogenetic and clinical precedents, they also examined effects of pregnant levels of human chorionic gonadotropin (hCG) on MSCs. They found effects similar to those of FSH, and RNAi knockdown of FSH-R abrogated both FSH and hCG effects on MSCs. In contrast to effects on MSCs, neither FSH nor hCG had significant effects on osteoblast maturation. Also in MSCs, short-term treatment by FSH and hCG altered signaling pathways for proliferation, including Erk1/2 phosphorylation.

Fig3. A much greater proportion of bone was double labeled in the FSH-R−/− animal.

Fig4. FSH-R protein in MSCs.

FSHR has several biochemical functions, for example, G-protein coupled peptide receptor activity,follicle-stimulating hormone receptor activity,protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by FSHR itself. We selected most functions FSHR had, and list some proteins which have the same functions with FSHR. You can find most of the proteins on our site.

FSHR has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with FSHR here. Most of them are supplied by our site. Hope this information will be useful for your research of FSHR.

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