Thyrotropin receptor explained

The thyrotropin receptor (or TSH receptor) is a receptor (and associated protein) that responds to thyroid-stimulating hormone (also known as "thyrotropin") and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins^[1] and is coupled to the G_s protein.^[2]

It is primarily found on the surface of the thyroid epithelial cells, but also found on adipose tissue and fibroblasts. The latter explains the reason of the myxedema finding during Graves disease. In addition, it has also been found to be expressed in the anterior pituitary gland, hypothalamus and kidneys. Its presence in the anterior pituitary gland may be involved in mediating the paracrine signaling feedback inhibition of thyrotropin along the hypothalamus-pituitary-thyroid axis.^[3]

Function

Upon binding circulating TSH, a G-protein signal cascade activates adenylyl cyclase and intracellular levels of cAMP rise. cAMP activates all functional aspects of the thyroid cell, including iodine pumping; thyroglobulin synthesis, iodination, endocytosis, and proteolysis; thyroid peroxidase activity; and hormone release. TSHR is involved in regulating seasonal reproduction in vertebrates.^[4]

See also

• Graves' disease

Further reading

• Führer D, Wonerow P, Willgerodt H, Paschke R . Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism . The Journal of Clinical Endocrinology and Metabolism . 82 . 12 . 4234–8 . Dec 1997 . 10.1210/jcem.82.12.4405 . 9398746 . free .
• Farid NR, Kascur V, Balazs C . The human thyrotropin receptor is highly mutable: a review of gain-of-function mutations . European Journal of Endocrinology. 143 . 1 . 25–30 . Jul 2000 . 10870027 . 10.1530/eje.0.1430025 . free .
• Szkudlinski MW, Fremont V, Ronin C, Weintraub BD . Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships . Physiological Reviews . 82 . 2 . 473–502 . Apr 2002 . 11917095 . 10.1152/physrev.00031.2001 . 2919509 .
• Tonacchera M, Vitti P, De Servi M, Agretti P, De Marco G, Chiovato L, Pinchera A . Gain of function TSH receptor mutations and iodine deficiency: implications in iodine prophylaxis . . 26 . 2 Suppl . 2–6 . 2004 . 12762632 .
• Arturi F, Scarpelli D, Coco A, Sacco R, Bruno R, Filetti S, Russo D . Thyrotropin receptor mutations and thyroid hyperfunctioning adenomas ten years after their first discovery: unresolved questions . Thyroid . 13 . 4 . 341–3 . Apr 2003 . 12804102 . 10.1089/105072503321669811 .
• Vaidya B, Campbell V, Tripp JH, Spyer G, Hattersley AT, Ellard S . Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation . Clinical Endocrinology . 60 . 6 . 711–8 . Jun 2004 . 15163335 . 10.1111/j.1365-2265.2004.02040.x . 43902851 .
• Takeshita A, Nagayama Y, Fujiyama K, Yokoyama N, Namba H, Yamashita S, Izumi M, Nagataki S . Molecular cloning and sequencing of an alternatively spliced form of the human thyrotropin receptor transcript . Biochemical and Biophysical Research Communications . 188 . 3 . 1214–9 . Nov 1992 . 1445355 . 10.1016/0006-291X(92)91360-3 .
• Graves PN, Tomer Y, Davies TF . Cloning and sequencing of a 1.3 KB variant of human thyrotropin receptor mRNA lacking the transmembrane domain . Biochemical and Biophysical Research Communications . 187 . 2 . 1135–43 . Sep 1992 . 1530609 . 10.1016/0006-291X(92)91315-H .
• Loosfelt H, Pichon C, Jolivet A, Misrahi M, Caillou B, Jamous M, Vannier B, Milgrom E . Two-subunit structure of the human thyrotropin receptor . Proceedings of the National Academy of Sciences of the United States of America . 89 . 9 . 3765–9 . May 1992 . 1570295 . 525571 . 10.1073/pnas.89.9.3765 . 1992PNAS...89.3765L . free .
• Nagayama Y, Russo D, Wadsworth HL, Chazenbalk GD, Rapoport B . Eleven amino acids (Lys-201 to Lys-211) and 9 amino acids (Gly-222 to Leu-230) in the human thyrotropin receptor are involved in ligand binding . The Journal of Biological Chemistry . 266 . 23 . 14926–30 . Aug 1991 . 10.1016/S0021-9258(18)98566-2 . 1651314 . free .
• Murakami M, Mori M . Identification of immunogenic regions in human thyrotropin receptor for immunoglobulin G of patients with Graves' disease . Biochemical and Biophysical Research Communications . 171 . 1 . 512–8 . Aug 1990 . 1697467 . 10.1016/0006-291X(90)91423-P .
• Heldin NE, Gustavsson B, Westermark K, Westermark B . A somatic point mutation in a putative ligand binding domain of the TSH receptor in a patient with autoimmune hyperthyroidism . The Journal of Clinical Endocrinology and Metabolism . 73 . 6 . 1374–6 . Dec 1991 . 1955520 . 10.1210/jcem-73-6-1374 .
• Libert F, Passage E, Lefort A, Vassart G, Mattei MG . Localization of human thyrotropin receptor gene to chromosome region 14q3 by in situ hybridization . Cytogenetics and Cell Genetics . 54 . 1–2 . 82–3 . 1991 . 2249482 . 10.1159/000132964 .
• Frazier AL, Robbins LS, Stork PJ, Sprengel R, Segaloff DL, Cone RD . Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing . Molecular Endocrinology . 4 . 8 . 1264–76 . Aug 1990 . 2293030 . 10.1210/mend-4-8-1264 . free . 21.11116/0000-0000-7844-D . free .
• Misrahi M, Loosfelt H, Atger M, Sar S, Guiochon-Mantel A, Milgrom E . Cloning, sequencing and expression of human TSH receptor . Biochemical and Biophysical Research Communications . 166 . 1 . 394–403 . Jan 1990 . 2302212 . 10.1016/0006-291X(90)91958-U .
• Nagayama Y, Kaufman KD, Seto P, Rapoport B . Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor . Biochemical and Biophysical Research Communications . 165 . 3 . 1184–90 . Dec 1989 . 2558651 . 10.1016/0006-291X(89)92727-7 .
• Libert F, Lefort A, Gerard C, Parmentier M, Perret J, Ludgate M, Dumont JE, Vassart G . Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: evidence for binding of autoantibodies . Biochemical and Biophysical Research Communications . 165 . 3 . 1250–5 . Dec 1989 . 2610690 . 10.1016/0006-291X(89)92736-8 .
• Cuddihy RM, Bryant WP, Bahn RS . Normal function in vivo of a homozygotic polymorphism in the human thyrotropin receptor . Thyroid . 5 . 4 . 255–7 . Aug 1995 . 7488864 . 10.1089/thy.1995.5.255 .
• Bahn RS, Dutton CM, Heufelder AE, Sarkar G . A genomic point mutation in the extracellular domain of the thyrotropin receptor in patients with Graves' ophthalmopathy . The Journal of Clinical Endocrinology and Metabolism . 78 . 2 . 256–60 . Feb 1994 . 10.1210/jcem.78.2.7508946 . 7508946 .
• Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S . Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene . The New England Journal of Medicine . 332 . 3 . 155–60 . Jan 1995 . 7528344 . 10.1056/NEJM199501193320305 . free .

External links

• Web site: Glycoprotein Hormone Receptors: TSH . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2007-10-25 . 2013-11-01 . https://web.archive.org/web/20131101121058/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2988 . dead .
  • SSFA-GPHR: Sequence Structure Function Analysis of Glycoprotein Hormone Receptors
• GRIS: Glycoprotein-hormone Receptor Information System

Notes and References

1. Farid NR, Szkudlinski MW . Minireview: structural and functional evolution of the thyrotropin receptor . Endocrinology . 145 . 9 . 4048–57 . Sep 2004 . 15231707 . 10.1210/en.2004-0437 . free .
2. Calebiro D, Nikolaev VO, Lohse MJ . Imaging of persistent cAMP signaling by internalized G protein-coupled receptors . Journal of Molecular Endocrinology . 45 . 1 . 1–8 . Jul 2010 . 20378719 . 10.1677/JME-10-0014 . free .
3. Williams GR . Extrathyroidal expression of TSH receptor . Annales d'Endocrinologie . 72 . 2 . 68–73 . April 2011 . 21511243 . 10.1016/j.ando.2011.03.006 . 54es Journees internationales d'Endocrinologie clinique .
4. Nakane Y, Yoshimura T . Photoperiodic Regulation of Reproduction in Vertebrates . Annual Review of Animal Biosciences . 7 . 1 . 173–194 . February 2019 . 30332291 . 10.1146/annurev-animal-020518-115216 . 52984435 .