Follicle-stimulating hormone receptor

Follicle stimulating hormone receptor
PDB rendering based on 4AY9.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1XUN​, 1XWD​, 4AY9​, 4MQW​
Identifiers
Symbols	FSHR ; FSHR1; FSHRO; LGR1; ODG1
External IDs	OMIM: 136435 MGI: 95583 HomoloGene: 117 IUPHAR: 253 ChEMBL: 2024 GeneCards: FSHR Gene
Gene ontology Molecular function • follicle-stimulating hormone receptor activity • protein binding • G-protein coupled peptide receptor activity Cellular component • plasma membrane • integral component of plasma membrane • integral component of membrane Biological process • primary ovarian follicle growth • G-protein coupled receptor signaling pathway • adenylate cyclase-activating G-protein coupled receptor signaling pathway • activation of adenylate cyclase activity • spermatogenesis • female gamete generation • gonad development • male gonad development • female gonad development • hormone-mediated signaling pathway • follicle-stimulating hormone signaling pathway • regulation of osteoclast differentiation • uterus development Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2492	14309
Ensembl	ENSG00000170820	ENSMUSG00000032937
UniProt	P23945	P35378
RefSeq (mRNA)	NM_000145	NM_013523
RefSeq (protein)	NP_000136	NP_038551
Location (UCSC)	Chr 2: 48.96 – 49.15 Mb	Chr 17: 88.99 – 89.2 Mb
PubMed search

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.

FSHR gene

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.^[1]

Receptor structure

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.^[1] 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.^[2] 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.^[3]
• 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.^[4]
• The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible 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.^[2] 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.

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 (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the FSH-receptor) via adenylate cyclase and 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 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.^[1]

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).^[5] 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 granulosa cells.^[1]

In the male, the FSH receptor has been identified on the Sertoli cells that are critical for spermatogenesis.^[6]

The FSHR is expressed during the luteal phase in the secretory endometrium of the uterus.^[7]

FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of carcinogenic tumors.^[8]

Receptor regulation

Upregulation

Upregulation refers to the increase in the number of receptor site 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.

Desensitization

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

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.

Modulators

Antibodies to FSHR can interfere with FSHR activity.

FSH abnormalities

Some patients with ovarian hyperstimulation syndrome may have mutations in the gene for FSHR, making them more sensitive to gonadotropin stimulation.^[9]

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.^[10]

Polymorphism may affect FSH receptor populations and lead to poorer responses in infertile women receiving FSH medication for IVF.^[11]

History

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

See also

• Luteinizing hormone/choriogonadotropin receptor

References

1. Simoni M, Gromoll J, Nieschlag E (Dec 1997). "The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology". Endocrine Reviews 18 (6): 739–73. doi:10.1210/er.18.6.739. PMID 9408742.
2. Jiang X, Liu H, Chen X, Chen PH, Fischer D, Sriraman V, Yu HN, Arkinstall S, He X (Jul 2012). "Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor". Proceedings of the National Academy of Sciences of the United States of America 109 (31): 12491–6. doi:10.1073/pnas.1206643109. PMID 22802634.
3. Costagliola S, Panneels V, Bonomi M, Koch J, Many MC, Smits G, Vassart G (Feb 2002). "Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors". The EMBO Journal 21 (4): 504–13. doi:10.1093/emboj/21.4.504. PMID 11847099.
4. Jiang X, Dias JA, He X (Jan 2014). "Structural biology of glycoprotein hormones and their receptors: insights to signaling". Molecular and Cellular Endocrinology 382 (1): 424–51. doi:10.1016/j.mce.2013.08.021. PMID 24001578.
5. Piketty V, Kara E, Guillou F, Reiter E, Crepieux P (2006). "Follicle-stimulating hormone (FSH) activates extracellular signal-regulated kinase phosphorylation independently of beta-arrestin- and dynamin-mediated FSH receptor internalization". Reproductive Biology and Endocrinology 4: 33. doi:10.1186/1477-7827-4-33. PMC 1524777. PMID 16787538.
6. Asatiani K, Gromoll J, Eckardstein SV, Zitzmann M, Nieschlag E, Simoni M (Jun 2002). "Distribution and function of FSH receptor genetic variants in normal men". Andrologia 34 (3): 172–6. doi:10.1046/j.1439-0272.2002.00493.x. PMID 12059813.
7. 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. PMID 16390776.
8. Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, Fromont G, Hai MT, Ghinea N (Oct 2010). "Expression of follicle-stimulating hormone receptor in tumor blood vessels". The New England Journal of Medicine 363 (17): 1621–30. doi:10.1056/NEJMoa1001283. PMID 20961245.
9. Delbaere A, Smits G, De Leener A, Costagliola S, Vassart G (Apr 2005). "Understanding ovarian hyperstimulation syndrome". Endocrine 26 (3): 285–90. doi:10.1385/ENDO:26:3:285. PMID 16034183.
10. Aittomäki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila EM, Lehväslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A (Sep 1995). "Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure". Cell 82 (6): 959–68. doi:10.1016/0092-8674(95)90275-9. PMID 7553856.
11. Loutradis D, Patsoula E, Minas V, Koussidis GA, Antsaklis A, Michalas S, Makrigiannakis A (Apr 2006). "FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs". Journal of Assisted Reproduction and Genetics 23 (4): 177–84. doi:10.1007/s10815-005-9015-z. PMC 3454958. PMID 16758348.

Further reading

• de la Chapelle A (Oct 1993). "Disease gene mapping in isolated human populations: the example of Finland". Journal of Medical Genetics 30 (10): 857–65. doi:10.1136/jmg.30.10.857. PMC 1016570. PMID 8230163.
• Amsterdam A, Hanoch T, Dantes A, Tajima K, Strauss JF, Seger R (Feb 2002). "Mechanisms of gonadotropin desensitization". Molecular and Cellular Endocrinology 187 (1-2): 69–74. doi:10.1016/S0303-7207(01)00701-8. PMID 11988313.
• Simoni M, Nieschlag E, Gromoll J (2003). "Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction". Human Reproduction Update 8 (5): 413–21. doi:10.1093/humupd/8.5.413. PMID 12398222.
• Delbaere A, Smits G, Olatunbosun O, Pierson R, Vassart G, Costagliola S (Mar 2004). "New insights into the pathophysiology of ovarian hyperstimulation syndrome. What makes the difference between spontaneous and iatrogenic syndrome?". Human Reproduction 19 (3): 486–9. doi:10.1093/humrep/deh124. PMC 2891954. PMID 14998941.
• Bose CK (Aug 2005). "Role of nerve growth factor and FSH receptor in epithelial ovarian cancer". Reproductive Biomedicine Online 11 (2): 194–7. doi:10.1016/S1472-6483(10)60958-3. PMID 16168216.
• 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. PMID 17544358.
• 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. PMID 1301382.
• Tilly JL, Aihara T, Nishimori K, Jia XC, Billig H, Kowalski KI, Perlas EA, Hsueh AJ (Aug 1992). "Expression of recombinant human follicle-stimulating hormone receptor: species-specific ligand binding, signal transduction, and identification of multiple ovarian messenger ribonucleic acid transcripts". Endocrinology 131 (2): 799–806. doi:10.1210/en.131.2.799. PMID 1322283.
• 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. PMID 1359889.
• 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. PMID 1709010.
• 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. PMID 7916967.
• 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. PMID 7926278.
• 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. PMID 8432542.
• Jiang X, Dreano M, Buckler DR, Cheng S, Ythier A, Wu H, Hendrickson WA, el Tayar N (Dec 1995). "Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions". Structure 3 (12): 1341–53. doi:10.1016/S0969-2126(01)00272-6. PMID 8747461.
• Aittomäki K, Herva R, Stenman UH, Juntunen K, Ylöstalo P, Hovatta O, de la Chapelle A (Oct 1996). "Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene". The Journal of Clinical Endocrinology and Metabolism 81 (10): 3722–6. doi:10.1210/jc.81.10.3722. PMID 8855829.
• 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. PMID 9020851.
• Kotlar TJ, Young RH, Albanese C, Crowley WF, Scully RE, Jameson JL (Apr 1997). "A mutation in the follicle-stimulating hormone receptor occurs frequently in human ovarian sex cord tumors". The Journal of Clinical Endocrinology and Metabolism 82 (4): 1020–6. doi:10.1210/jc.82.4.1020. PMID 9100567.

External links

• "Glycoprotein Hormone Receptors: FSH". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• GRIS: Glycoprotein-hormone Receptor Information System