Follicle-stimulating hormone receptor

Protein coding gene in the species Homo sapiens

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

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

The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa. 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 cysteine residues that build 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 glycoprotein hormone receptor members (LHR and TSHR), this conserved triplet motif is a variation Glu Arg Trp sequence. The C terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.

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. 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.

In the ovary, the FSH receptor is necessary for follicular development and expressed on the granulosa cells. The FSHR is expressed during the luteal phase in the secretory endometrium of the uterus. FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of carcinogenic tumors.

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

The FSHR become desensitized when exposed to FSH for some time. A key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by 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 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 clathrins. A pinched off coated pit is internalized and degraded by lysosomes. Proteins may be metabolized or the receptor can be recycled. Use of long acting agonists will downregulate the receptor population.

Antibodies to FSHR can interfere with FSHR activity.

Follicle stimulating hormone (FSH) is an agonist of the FSHR. Small molecule positive allosteric modulators of the FSHR have been developed.

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