Follicle-stimulating hormone receptor

The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a is_associated_with::transmembrane receptor that interacts with the is_associated_with::follicle-stimulating hormone (FSH) and represents a is_associated_with::G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the is_associated_with::ovary, is_associated_with::testis, and is_associated_with::uterus.

FSHR gene
The gene for the FSHR is found on is_associated_with::chromosome 2 p21 in humans. The gene sequence of the FSHR consists of about 2,080 is_associated_with::nucleotides.

Receptor structure


The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa. Like other GPCRs, the FSH-receptor possesses seven membrane-spanning domains or transmembrane helices.


 * The extracellular domain of the receptor contains 11 leucine-rich repeats and is glycosylated. It has two subdomains, a hormone-binding subdomain followed by a signal-specificity subdomain.  The hormone-binding subdomain is responsible for the high-affinity hormone binding, and the signal-specificity subdomain, containing a sulfated tyrosine at position 335 (sTyr) in a hinge loop, is required for the hormone activity.


 * The transmembrane domain contains two highly conserved is_associated_with::cysteine residues that build is_associated_with::disulfide bonds to stabilize the receptor structure. A highly conserved Asp-Arg-Tyr triplet motif is present in GPCR family members in general and may be of importance to transmit the signal. In FSHR and its closely related other is_associated_with::glycoprotein hormone receptor members (LHR and is_associated_with::TSHR), this conserved triplet motif is a variation Glu-Arg-Trp sequence.


 * The C-terminal domain is intracellular and brief, rich in is_associated_with::serine and is_associated_with::threonine residues for possible is_associated_with::phosphorylation.

Ligand binding and signal transduction
Upon initial binding to the LRR region of FSHR, FSH reshapes its conformation to form a new pocket. FSHR then inserts its sulfotyrosine from the hinge loop into the pockets and activates the 7-helical transmembrane domain. This event leads to a transduction of the signal that activates the is_associated_with::G protein that is bound to the receptor internally. With FSH attached, the receptor shifts conformation and, thus, mechanically activates the G protein, which detaches from the receptor and activates the cAMP system.

It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of FSH to the receptor shifts the equilibrium between active and inactive receptors. FSH and FSH-agonists shift the equilibrium in favor of active states; FSH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to FSH, only a small percentage (~1%) of receptor sites need to be activated.

Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (is_associated_with::protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the FSH-receptor) via is_associated_with::adenylate cyclase and is_associated_with::cyclic AMP (cAMP). These protein kinases are present as tetramers with two regulatory units and two catalytic units. Upon binding of cAMP to the regulatory units, the catalytic units are released and initiate the phosphorylation of proteins, leading to the physiologic action. The cyclic AMP-regulatory dimers are degraded by is_associated_with::phosphodiesterase and release 5’AMP. is_associated_with::DNA in the is_associated_with::cell nucleus  binds to phosphorylated proteins through the is_associated_with::cyclic AMP response element (CRE), which results in the activation of is_associated_with::genes.

The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by is_associated_with::prostaglandins. Other cellular regulators are participate are the intracellular calcium concentration modified by is_associated_with::phospholipase, is_associated_with::nitric acid, and other growth factors.

The FSH receptor can also activate the is_associated_with::extracellular signal-regulated kinases (ERK). In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active, the more kinases are activated, the more receptors are phosphorylated.

Action
In the ovary, the FSH receptor is necessary for follicular development and expressed on the is_associated_with::granulosa cells.

In the male, the FSH receptor has been identified on the is_associated_with::Sertoli cells that are critical for is_associated_with::spermatogenesis.

The FSHR is expressed during the luteal phase in the secretory is_associated_with::endometrium of the uterus.

FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of carcinogenic tumors.

Upregulation
is_associated_with::Upregulation refers to the increase in the number of receptor site on the membrane. Estrogen upregulates FSH receptor sites. In turn, FSH stimulates is_associated_with::granulosa cells to produce is_associated_with::estrogens. This synergistic activity of estrogen and FSH allows for follicle growth and development in the ovary.

Desensitization
The FSHR become desensitized when exposed to FSH for some time. A key reaction of this downregulation is the is_associated_with::phosphorylation of the intracellular (or is_associated_with::cytoplasmic) receptor domain by is_associated_with::protein kinases. This process uncouples Gs protein from the FSHR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.

Downregulation
is_associated_with::Downregulation refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound FSHR sites. The bound FSH-receptor complex is brought by lateral migration to a "coated pit," where such units are concentrated and then stabilized by a framework of is_associated_with::clathrins. A pinched-off coated pit is internalized and degraded by is_associated_with::lysosomes. Proteins may be metabolized or the receptor can be recycled. Use of long-acting agonists will downregulate the receptor population.

Modulators
Antibodies to FSHR can interfere with FSHR activity.

FSH abnormalities
Some patients with is_associated_with::ovarian hyperstimulation syndrome may have is_associated_with::mutations in the gene for FSHR, making them more sensitive to gonadotropin stimulation.

Women with 46 is_associated_with::XX gonadal dysgenesis experience primary is_associated_with::amenorrhea with hypergonadotropic is_associated_with::hypogonadism. There are forms of 46 xx gonadal dysgenesis wherein abnormalities  in the FSH-receptor have been reported and are thought to be the cause of the hypogonadism.

Polymorphism may affect FSH receptor populations and lead to poorer responses in infertile women receiving FSH medication for is_associated_with::IVF.

History
is_associated_with::Alfred G. Gilman and is_associated_with::Martin Rodbell received the 1994 is_associated_with::Nobel Prize in Medicine and Physiology for the discovery of the G Protein System.