Top ▲
Gene and Protein Information  |
||||||
| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 764 | 14q24-q31 | TSHR | thyroid stimulating hormone receptor | 28,31 |
| Mouse | 7 | 764 | 12 44.51 cM | Tshr | thyroid stimulating hormone receptor | 48 |
| Rat | 7 | 764 | 6q31 | Tshr | thyroid stimulating hormone receptor | 1 |
| Previous and Unofficial Names |
| Thyrotropin Receptor | LGR3 | TSH-R |
| Database Links |
|
| Specialist databases | |
| GPCRdb | tshr_human (Hs), tshr_mouse (Mm), tshr_rat (Rn) |
| Other databases | |
| Alphafold | P16473 (Hs), P47750 (Mm), P21463 (Rn) |
| CATH/Gene3D | 3.80.10.10 |
| ChEMBL Target | CHEMBL1963 (Hs) |
| DrugBank Target | P16473 (Hs) |
| Ensembl Gene | ENSG00000165409 (Hs), ENSMUSG00000020963 (Mm), ENSRNOG00000003972 (Rn) |
| Entrez Gene | 7253 (Hs), 22095 (Mm), 25360 (Rn) |
| Human Protein Atlas | ENSG00000165409 (Hs) |
| KEGG Gene | hsa:7253 (Hs), mmu:22095 (Mm), rno:25360 (Rn) |
| OMIM | 603372 (Hs) |
| Orphanet | ORPHA120320 (Hs) |
| Pharos | P16473 (Hs) |
| RefSeq Nucleotide | NM_000369 (Hs), NM_011648 (Mm), NM_012888 (Rn) |
| RefSeq Protein | NP_000360 (Hs), NP_035778 (Mm), NP_037020 (Rn) |
| UniProtKB | P16473 (Hs), P47750 (Mm), P21463 (Rn) |
| Wikipedia | TSHR (Hs) |
| Natural/Endogenous Ligands |
| TSH {Sp: Human} , TSH {Sp: Mouse} , TSH {Sp: Rat} |
| Potency order of endogenous ligands |
| TSH (CGA, TSHB, P01215, P01222) |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The TSH receptor is the primary target for the approved drug thyrotropin alfa, a recombinant form of the endogenous peptide. Human TSH (thyrotropin) displays much lower binding affinity and lower potency than bovine TSH [39] on the human and other mammalian TSH receptors, making it impossible to measure Kd. This may be correlated to the evolutionary appearance of hCG in primates [50]. Murine [4,8-9,46] and human [45] stimulating monoclonal antibodies and human thyrostimulin [32] are also TSH receptor agonists. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonist Comments | ||
| Murine blocking monoclonal antibodies are TSH receptor antagonists [8,44]. |
| Immuno Process Associations | ||
|
||
|
||
|
| Primary Transduction Mechanisms
|
|
| Transducer | Effector/Response |
| Gs family | Adenylyl cyclase stimulation |
| Comments: In the human species, stimulation of the Gs regulatory cascade positively controls the function (secretion of thyroid hormones) and the growth of thyrocytes. Continuous basal stimulation of this cascade is required to maintain the differentiation state of the thyroid gland. | |
| References: 3 | |
| Secondary Transduction Mechanisms |
|
| Transducer | Effector/Response |
| Gq/G11 family | Phospholipase C stimulation |
| Comments: Stimulation of the Gq cascade is associated in the human species with H2O2 production, which is required for activation of thyroid hormone synthesis. | |
| References: 3 | |
| Tissue Distribution
|
||||||||
|
||||||||
|
||||||||
| Tissue Distribution Comments | ||||||||
| The major site of expression for the TSH receptor is the thyroid gland [28,31]. Receptor transcripts found in extrathyroid tissues have, at present, undefined function [57]. | ||||||||
| Expression Datasets |
|
|
| Functional Assays
|
||||||||||
|
||||||||||
|
| Physiological Functions
|
||||||||
|
||||||||
|
||||||||
|
| Physiological Consequences of Altering Gene Expression
|
||||||||||
|
| Phenotypes, Alleles and Disease Models
|
Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinically-Relevant Mutations and Pathophysiology
|
||||||||||||||
|
||||||||||||||
|
||||||||||||||
|
||||||||||||||
|
||||||||||||||
|
||||||||||||||
| Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||
| TSHR is also associated with the phenotypes of somatic, hyperfunctioning thyroid adenoma, and thyroid carcinoma with thyrotoxicosis. For more details see the OMIM entry linked to from the table of database links above. | ||||||||||||||
| Biologically Significant Variants
|
||||||||
|
||||||||
|
1. Akamizu T, Ikuyama S, Saji M, Kosugi S, Kozak C, McBride OW, Kohn LD. (1990) Cloning, chromosomal assignment, and regulation of the rat thyrotropin receptor: expression of the gene is regulated by thyrotropin, agents that increase cAMP levels, and thyroid autoantibodies. Proc Natl Acad Sci USA, 87 (15): 5677-81. [PMID:1696008]
2. Alberti L, Proverbio MC, Costagliola S, Romoli R, Boldrighini B, Vigone MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L. (2002) Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab, 87 (6): 2549-55. [PMID:12050212]
3. Allgeier A, Offermanns S, Van Sande J, Spicher K, Schultz G, Dumont JE. (1994) The human thyrotropin receptor activates G-proteins Gs and Gq/11. J Biol Chem, 269 (19): 13733-5. [PMID:8188646]
4. Ando T, Latif R, Pritsker A, Moran T, Nagayama Y, Davies TF. (2002) A monoclonal thyroid-stimulating antibody. J Clin Invest, 110 (11): 1667-74. [PMID:12464672]
5. Biebermann H, Schöneberg T, Krude H, Gudermann T, Grüters A. (2000) Constitutively activating TSH-receptor mutations as a molecular cause of non-autoimmune hyperthyroidism in childhood. Langenbecks Arch Surg, 385: 390-392. [PMID:11127522]
6. Biebermann H, Schöneberg T, Schulz A, Krause G, Grüters A, Schultz G, Gudermann T. (1998) A conserved tyrosine residue (Y601) in transmembrane domain 5 of the human thyrotropin receptor serves as a molecular switch to determine G-protein coupling. FASEB J, 12 (14): 1461-71. [PMID:9806755]
7. Clifton-Bligh RJ, Gregory JW, Ludgate M, John R, Persani L, Asteria C, Beck-Peccoz P, Chatterjee VK. (1997) Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH. J Clin Endocrinol Metab, 82: 1094-1100. [PMID:9100579]
8. Costagliola S, Bonomi M, Morgenthaler NG, Van Durme J, Panneels V, Refetoff S, Vassart G. (2004) Delineation of the discontinuous-conformational epitope of a monoclonal antibody displaying full in vitro and in vivo thyrotropin activity. Mol Endocrinol, 18 (12): 3020-34. [PMID:15319453]
9. Costagliola S, Franssen JD, Bonomi M, Urizar E, Willnich M, Bergmann A, Vassart G. (2002) Generation of a mouse monoclonal TSH receptor antibody with stimulating activity. Biochem Biophys Res Commun, 299 (5): 891-6. [PMID:12470663]
10. Crisanti P, Omri B, Hughes E, Meduri G, Hery C, Clauser E, Jacquemin C, Saunier B. (2001) The expression of thyrotropin receptor in the brain. Endocrinology, 142: 812-822. [PMID:11159854]
11. de Roux N, Misrahi M, Brauner R, Houang M, Carel JC, Granier M, Le Bouc Y, Ghinea N, Boumedienne A, Toublanc JE et al.. (1996) Four families with loss of function mutations of the thyrotropin receptor. J Clin Endocrinol Metab, 81 (12): 4229-35. [PMID:8954020]
12. de Roux N, Polak M, Couet J, Leger J, Czernichow P, Milgrom E, Misrahi M. (1996) A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J Clin Endocrinol Metab, 81 (6): 2023-6. [PMID:8964822]
13. Duprez L, Parma J, Costagliola S, Hermans J, Van Sande J, Dumont JE, Vassart G. (1997) Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain. FEBS Lett, 409 (3): 469-74. [PMID:9224711]
14. Duprez L, Parma J, Van Sande J, Allgeier A, Leclère J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont J et al.. (1994) Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet, 7 (3): 396-401. [PMID:7920658]
15. Englund EE, Neumann S, Eliseeva E, McCoy JG, Titus S, Zheng W, Southall N, Shin P, Leister W, Thomas CJ et al.. (2011) The Synthesis and Evaluation of Dihydroquinazolin-4-ones and Quinazolin-4-ones as Thyroid Stimulating Hormone Receptor Agonists. Medchemcomm, 2 (10): 1016-1020. [PMID:22408719]
16. Esapa CT, Duprez L, Ludgate M, Mustafa MS, Kendall-Taylor P, Vassart G, Harris PE. (1999) A novel thyrotropin receptor mutation in an infant with severe thyrotoxicosis. Thyroid, 9 (10): 1005-10. [PMID:10560955]
17. Führer D, Holzapfel HP, Wonerow P, Scherbaum WA, Paschke R. (1997) Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab, 82 (11): 3885-91. [PMID:9360556]
18. Führer D, Wonerow P, Willgerodt H, Paschke R. (1997) Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J Clin Endocrinol Metab, 82 (12): 4234-8. [PMID:9398746]
19. Gagné N, Parma J, Deal C, Vassart G, Van Vliet G. (1998) Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities?. J Clin Endocrinol Metab, 83 (5): 1771-5. [PMID:9589691]
20. Grüters A, Schöneberg T, Biebermann H, Krude H, Krohn HP, Dralle H, Gudermann T. (1998) Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J Clin Endocrinol Metab, 83 (5): 1431-6. [PMID:9589634]
21. Holzapfel HP, Führer D, Wonerow P, Weinland G, Scherbaum WA, Paschke R. (1997) Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters. J Clin Endocrinol Metab, 82 (12): 4229-33. [PMID:9398745]
22. Holzapfel HP, Wonerow P, von Petrykowski W, Henschen M, Scherbaum WA, Paschke R. (1997) Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab, 82 (11): 3879-84. [PMID:9360555]
23. Jordan N, Williams N, Gregory JW, Evans C, Owen M, Ludgate M. (2003) The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population. J Clin Endocrinol Metab, 88 (3): 1002-5. [PMID:12629076]
24. Kopp P, Muirhead S, Jourdain N, Gu WX, Jameson JL, Rodd C. (1997) Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281-->isoleucine) in the extracellular domain of the thyrotropin receptor. J Clin Invest, 100 (6): 1634-9. [PMID:9294132]
25. Kosugi S, Hai N, Okamoto H, Sugawa H, Mori T. (2000) A novel activating mutation in the thyrotropin receptor gene in an autonomously functioning thyroid nodule developed by a Japanese patient. Eur J Endocrinol, 143 (4): 471-7. [PMID:11022192]
26. Krohn K, Führer D, Holzapfel HP, Paschke R. (1998) Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J Clin Endocrinol Metab, 83 (1): 130-4. [PMID:9435429]
27. Lee YS, Poh L, Loke KY. (2002) An activating mutation of the thyrotropin receptor gene in hereditary non-autoimmune hyperthyroidism. J Pediatr Endocrinol Metab, 15 (2): 211-5. [PMID:11874187]
28. Libert F, Lefort A, Gerard C, Parmentier M, Perret J, Ludgate M, Dumont JE, Vassart G. (1989) Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: evidence for binding of autoantibodies. Biochem Biophys Res Commun, 165: 1250-1255. [PMID:2610690]
29. Marians RC, Ng L, Blair HC, Unger P, Graves PN, Davies TF. (2002) Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice. Proc Natl Acad Sci USA, 99 (24): 15776-81. [PMID:12432094]
30. Nagashima T, Murakami M, Onigata K, Morimura T, Nagashima K, Mori M, Morikawa A. (2001) Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin. Thyroid, 11 (6): 551-9. [PMID:11442002]
31. Nagayama Y, Kaufman KD, Seto P, Rapoport B. (1989) Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem Biophys Res Commun, 165 (3): 1184-90. [PMID:2558651]
32. Nakabayashi K, Matsumi H, Bhalla A, Bae J, Mosselman S, Hsu SY, Hsueh AJ. (2002) Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. J Clin Invest, 109 (11): 1445-52. [PMID:12045258]
33. Park SM, Clifton-Bligh RJ, Betts P, Chatterjee VK. (2004) Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor. Clin Endocrinol (Oxf), 60 (2): 220-7. [PMID:14725684]
34. Parma J, Duprez L, Van Sande J, Hermans J, Rocmans P, Van Vliet G, Costagliola S, Rodien P, Dumont JE, Vassart G. (1997) Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab, 82: 2695-2701. [PMID:9253356]
35. Paschke R, Tonacchera M, Van Sande J, Parma J, Vassart G. (1994) Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid. J Clin Endocrinol Metab, 79 (6): 1785-9. [PMID:7989485]
36. Perret J, Ludgate M, Libert F, Gerard C, Dumont JE, Vassart G, Parmentier M. (1990) Stable expression of the human TSH receptor in CHO cells and characterization of differentially expressing clones. Biochem Biophys Res Commun, 171 (3): 1044-50. [PMID:2171505]
37. Persani L, Lania A, Alberti L, Romoli R, Mantovani G, Filetti S, Spada A, Conti M. (2000) Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas. J Clin Endocrinol Metab, 85 (8): 2872-8. [PMID:10946896]
38. Postiglione MP, Parlato R, Rodriguez-Mallon A, Rosica A, Mithbaokar P, Maresca M, Marians RC, Davies TF, Zannini MS, De Felice M et al.. (2002) Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland. Proc Natl Acad Sci USA, 99 (24): 15462-7. [PMID:12432093]
39. Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. (1998) The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies. Endocr Rev, 19 (6): 673-716. [PMID:9861544]
40. Ringkananont U, Van Durme J, Montanelli L, Ugrasbul F, Yu YM, Weiss RE, Refetoff S, Grasberger H. (2006) Repulsive separation of the cytoplasmic ends of transmembrane helices 3 and 6 is linked to receptor activation in a novel thyrotropin receptor mutant (M626I). Mol Endocrinol, 20 (4): 893-903. [PMID:16339276]
41. Russo D, Arturi F, Schlumberger M, Caillou B, Monier R, Filetti S, Suárez HG. (1995) Activating mutations of the TSH receptor in differentiated thyroid carcinomas. Oncogene, 11 (9): 1907-11. [PMID:7478621]
42. Russo D, Betterle C, Arturi F, Chiefari E, Girelli ME, Filetti S. (2000) A novel mutation in the thyrotropin (TSH) receptor gene causing loss of TSH binding but constitutive receptor activation in a family with resistance to TSH. J Clin Endocrinol Metab, 85 (11): 4238-42. [PMID:11095460]
43. Russo D, Wong MG, Costante G, Chiefari E, Treseler PA, Arturi F, Filetti S, Clark OH. (1999) A Val 677 activating mutation of the thyrotropin receptor in a Hürthle cell thyroid carcinoma associated with thyrotoxicosis. Thyroid, 9 (1): 13-7. [PMID:10037070]
44. Sanders J, Allen F, Jeffreys J, Bolton J, Richards T, Depraetere H, Nakatake N, Evans M, Kiddie A, Premawardhana LD et al.. (2005) Characteristics of a monoclonal antibody to the thyrotropin receptor that acts as a powerful thyroid-stimulating autoantibody antagonist. Thyroid, 15 (7): 672-82. [PMID:16053383]
45. Sanders J, Evans M, Premawardhana LD, Depraetere H, Jeffreys J, Richards T, Furmaniak J, Rees Smith B. (2003) Human monoclonal thyroid stimulating autoantibody. Lancet, 362 (9378): 126-8. [PMID:12867115]
46. Sanders J, Jeffreys J, Depraetere H, Richards T, Evans M, Kiddie A, Brereton K, Groenen M, Oda Y, Furmaniak J et al.. (2002) Thyroid-stimulating monoclonal antibodies. Thyroid, 12 (12): 1043-50. [PMID:12593717]
47. Smits G, Govaerts C, Nubourgh I, Pardo L, Vassart G, Costagliola S. (2002) Lysine 183 and glutamic acid 157 of the TSH receptor: two interacting residues with a key role in determining specificity toward TSH and human CG. Mol Endocrinol, 16 (4): 722-35. [PMID:11923469]
48. Stein SA, Oates EL, Hall CR, Grumbles RM, Fernandez LM, Taylor NA, Puett D, Jin S. (1994) Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse. Mol Endocrinol, 8 (2): 129-38. [PMID:8170469]
49. Sykiotis GP, Neumann S, Georgopoulos NA, Sgourou A, Papachatzopoulou A, Markou KB, Kyriazopoulou V, Paschke R, Vagenakis AG, Papavassiliou AG. (2003) Functional significance of the thyrotropin receptor germline polymorphism D727E. Biochem Biophys Res Commun, 301 (4): 1051-6. [PMID:12589819]
50. Szkudlinski MW, Fremont V, Ronin C, Weintraub BD. (2002) Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev, 82 (2): 473-502. [PMID:11917095]
51. Tonacchera M, Agretti P, Pinchera A, Rosellini V, Perri A, Collecchi P, Vitti P, Chiovato L. (2000) Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene. J Clin Endocrinol Metab, 85 (3): 1001-8. [PMID:10720030]
52. Tonacchera M, Chiovato L, Pinchera A, Agretti P, Fiore E, Cetani F, Rocchi R, Viacava P, Miccoli P, Vitti P. (1998) Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab, 83 (2): 492-8. [PMID:9467563]
53. Tonacchera M, Perri A, De Marco G, Agretti P, Banco ME, Di Cosmo C, Grasso L, Vitti P, Chiovato L, Pinchera A. (2004) Low prevalence of thyrotropin receptor mutations in a large series of subjects with sporadic and familial nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab, 89 (11): 5787-93. [PMID:15531543]
54. Tonacchera M, Van Sande J, Cetani F, Swillens S, Schvartz C, Winiszewski P, Portmann L, Dumont JE, Vassart G, Parma J. (1996) Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia. J Clin Endocrinol Metab, 81 (2): 547-54. [PMID:8636266]
55. Tonacchera M, Vitti P, Agretti P, Giulianetti B, Mazzi B, Cavaliere R, Ceccarini G, Fiore E, Viacava P, Naccarato A et al.. (1998) Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter. Thyroid, 8 (7): 559-64. [PMID:9709907]
56. Vitti P, Rotella CM, Valente WA, Cohen J, Aloj SM, Laccetti P, Ambesi-Impiombato FS, Grollman EF, Pinchera A, Toccafondi R et al.. (1983) Characterization of the optimal stimulatory effects of graves' monoclonal and serum immunoglobulin G on adenosine 3',5'-monophosphate production in fRTL-5 thyroid cells: a potential clinical assay. J Clin Endocrinol Metab, 57 (4): 782-91. [PMID:6136523]
57. Zhang W, Morris QD, Chang R, Shai O, Bakowski MA, Mitsakakis N, Mohammad N, Robinson MD, Zirngibl R, Somogyi E et al.. (2004) The functional landscape of mouse gene expression. J Biol, 3 (5): 21. [PMID:15588312]
