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.[5]
Receptor structure
[edit]The seven transmembrane α-helix structure of a G protein-coupled receptor such as FSHR
The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa.[5] 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.[6] 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.[7]
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.[8]
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.[6] This event leads to a transduction of the signal that activates the 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.[citation needed]
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.[citation needed]
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 phosphodiesterase and release 5’AMP. DNA in the cell nucleus binds to phosphorylated proteins through the cyclic AMP response element (CRE), which results in the activation of genes.[5]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandins. Other cellular regulators are participate are the intracellular calcium concentration modified by phospholipase, nitric acid, and other growth factors.
The FSH receptor can also activate the extracellular signal-regulated kinases (ERK).[9] 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.[citation needed]
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.[citation needed]
The FSHR become desensitized when exposed to FSH for some time. A key reaction of this downregulation is the phosphorylation of the intracellular (orcytoplasmic) 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.[citation needed]
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.[citation needed]
Women with 46 XX gonadal dysgenesis experience primary amenorrhea with hypergonadotropic 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.[14]
Polymorphism may affect FSH receptor populations and lead to poorer responses in infertile women receiving FSH medication for IVF.[15]
Alternative splicing of the FSHR gene may be implicated in subfertility in males[16]
^La Marca A, Carducci Artenisio A, Stabile G, Rivasi F, Volpe A (Dec 2005). "Evidence for cycle-dependent expression of follicle-stimulating hormone receptor in human endometrium". Gynecological Endocrinology. 21 (6): 303–6. doi:10.1080/09513590500402756. PMID16390776. S2CID24690912.
Wunsch A, Sonntag B, Simoni M (Jun 2007). "Polymorphism of the FSH receptor and ovarian response to FSH". Annales d'Endocrinologie. 68 (2–3): 160–6. doi:10.1016/j.ando.2007.04.006. PMID17544358.
Kelton CA, Cheng SV, Nugent NP, Schweickhardt RL, Rosenthal JL, Overton SA, Wands GD, Kuzeja JB, Luchette CA, Chappel SC (Nov 1992). "The cloning of the human follicle stimulating hormone receptor and its expression in COS-7, CHO, and Y-1 cells". Molecular and Cellular Endocrinology. 89 (1–2): 141–51. doi:10.1016/0303-7207(92)90220-Z. PMID1301382. S2CID25403860.
Gromoll J, Gudermann T, Nieschlag E (Nov 1992). "Molecular cloning of a truncated isoform of the human follicle stimulating hormone receptor". Biochemical and Biophysical Research Communications. 188 (3): 1077–83. doi:10.1016/0006-291X(92)91341-M. PMID1359889.
Minegishi T, Nakamura K, Takakura Y, Ibuki Y, Igarashi M, Minegishi T (Mar 1991). "Cloning and sequencing of human FSH receptor cDNA". Biochemical and Biophysical Research Communications. 175 (3): 1125–30. doi:10.1016/0006-291X(91)91682-3. PMID1709010.
Gromoll J, Ried T, Holtgreve-Grez H, Nieschlag E, Gudermann T (Jun 1994). "Localization of the human FSH receptor to chromosome 2 p21 using a genomic probe comprising exon 10". Journal of Molecular Endocrinology. 12 (3): 265–71. doi:10.1677/jme.0.0120265. PMID7916967.
Gromoll J, Dankbar B, Gudermann T (Jun 1994). "Characterization of the 5' flanking region of the human follicle-stimulating hormone receptor gene". Molecular and Cellular Endocrinology. 102 (1–2): 93–102. doi:10.1016/0303-7207(94)90102-3. PMID7926278. S2CID20112797.
Rousseau-Merck MF, Atger M, Loosfelt H, Milgrom E, Berger R (Jan 1993). "The chromosomal localization of the human follicle-stimulating hormone receptor gene (FSHR) on 2p21-p16 is similar to that of the luteinizing hormone receptor gene". Genomics. 15 (1): 222–4. doi:10.1006/geno.1993.1041. PMID8432542.
Tapanainen JS, Aittomäki K, Min J, Vaskivuo T, Huhtaniemi IT (Feb 1997). "Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility". Nature Genetics. 15 (2): 205–6. doi:10.1038/ng0297-205. PMID9020851. S2CID1068731.
"Glycoprotein Hormone Receptors: FSH". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2014-04-07. Retrieved 2006-07-20.
