Receptors of the Thyroid: The Thyrotropin Receptor is Only the First Violinist of a Symphony Orchestra

  • Leonard D. Kohn
  • Motoyasu Saji
  • Takashi Akamizu
  • Shoichiro Ikuyama
  • Osamu Isozaki
  • Aimee D. Kohn
  • Pilar Santisteban
  • John Y. Chan
  • Shashikumar Bellur
  • Carlo M. Rotella
  • Francisco V. Alvarez
  • Salvatore M. Aloj
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 261)


The primary role of the thyroid is to produce thyroid hormones; the primary regulator of the thyroid, both its function and growth, is the pituitary glycoprotein hormone, thyrotropin (TSH). Studies of the mechanism by which thyrotropin regulates thyroid cells have been a dominant part of thyroid research for the past several decades because autoantibodies to the TSH receptor have been implicated in the hyperfunction and goiter of autoimmune Graves’ disease. Understanding why the TSH receptor, but not receptors for other glycoprotein hormones, is an autoantigen is a major medical concern. Equally of concern has been the mechanism by which the TSH receptor achieves its The present report will try to show how TSH and its functional response and the relationship of TSH and its receptor to thyroid growth.


Cholera Toxin Malic Enzyme Thyroid Cell cAMP Signal Thyrotropin Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    G. A. Robison, R. W. Butcher and E. W. Sutherland, “Cyclic AMP,” Academic Press, New York (1971).Google Scholar
  2. 2.
    J. E. Dumont, The action of thyrotropin on thyroid metabolism, Vitam. Horm. (N. Y.), 29: 287 (1971).CrossRefGoogle Scholar
  3. 3.
    E. M. Ross and A. G. Gilman, Biochemical properties of hormone sensitive adenylate cyclase, Ann. Rev. Biochem., 49: 533 (1980).PubMedCrossRefGoogle Scholar
  4. 4.
    F. S. Ambesi-Impiombato, L. A. M. Parks and H. G. Coon, Culture of hormone dependent epithelial cells from rat thyroids, Proc. Natl. Acad. Sci. USA, 77: 3455 (1980).PubMedCrossRefGoogle Scholar
  5. 5.
    F. S. Ambesi-Impiombato, Living, fast-growing thyroid cell strain, FRTL-5. US Patent 4,608,341, August 26 (1986).Google Scholar
  6. 6.
    C. M. Rotella, F. V. Alvarez, N. Perrotti, L. D. Kohn and S. Taylor, Characterization of receptors for insulin and IGF-I on FRTL-5 thyroid cells, in: “Control of the Thyroid Gland: Regulation of its Normal Function and Growth,” Plenum Publishing Corp., New York (1989).Google Scholar
  7. 7.
    P. Santisteban, L. D. Kohn and R. DiLauro, Thyroglobulin gene expression is regulated by insulin and IGF-I, as well as thyrotropin, in FRTL5 thyroid cells, J. Biol. Chem., 262: 4048 (1987).PubMedGoogle Scholar
  8. 8.
    G. Van Heuverswyn, C. Streydio, H. Brocas, S. Refetoff, J. Dumont and G. Vassart, Thyrotropin controls transcription of the thyroglobulin gene, Proc. Natl. Acad. Sci. USA, 81: 5941 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    L. D. Kohn, W. A. Valente, E. F. Grollman, S. M. Aloj and P. Vitti, Clinical determination and/or quantification of thyrotropin and a variety of thyroid stimulatory or inhibitory factors performed in vitro with an improved thyroid cell line FRTL-5, US Patent 4,609,622, Sept 2 (1986).Google Scholar
  10. 10.
    O. Isozaki and L. D. Kohn, Control of c-fos and cmyc protooncogene induction in rat thyroid cells in culture, Mol. Endo., 1: 839 (1987).CrossRefGoogle Scholar
  11. 11.
    Y. Shishiba, M. Yanagashita and V. C. Hascall, Characterization of proteoglycans synthesized by rat thyroid cells in culture and their response to thyroid stimulating hormone, J. Biol. Chem., 263: 1745 (1987).Google Scholar
  12. 12.
    F. V. Alvarez, C. M. Rotella, W. A. Valente, J. Y. Chan, O. Isozaki, R. Toccafondi, A. D. Kohn and L. D. Kohn, Glycosaminoglycan synthesis in thyroid cells: stimulation by throtropin, insulin-like growth factor I, and IgG preparations from Graves’ patients with pretibial myxedema, in: “The Thyroid, 1988,” S. Nagataki and K. Torizuka, eds., Excerpta Medica Int. Cong. Series 796, Elsevier Science Publishers, Amsterdam (1988).Google Scholar
  13. 13.
    D. Corda, L. Iacovelli, and M. DiGirolamo, Coupling of the alpha 1•adrenergic receptor and thyrotropin receptors to second messenger systems in thyroid cells: role of G proteins, Horizons in Endocrinology, 52: 169 (1988).Google Scholar
  14. 14.
    F. Okajima, K. Sho and Y. Kondo, Inhibition by islet-activating protein, pertussis toxin, of P2purinergic receptor-mediated iodide efflux and phosphoinositide turnover in FRTL-5 cells, Endocrinology, 123: 1035 (1988).PubMedCrossRefGoogle Scholar
  15. 15.
    J. E. Fradkin, W. C. Hardy and J. Wolff, Adenosine receptor-mediated accumulation of cAMP in guinea pig thyroid tissue, Endocrinology, 110: 2018 (1982).PubMedCrossRefGoogle Scholar
  16. 16.
    L. D. Garren, R. D. Howell, G. M. Tomkins and R. M. Crocco, A paradoxical effect of actinomycin D: the mechanism of regulation of enzyme synthesis by hydrocortisone, Proc. Natl. Acad. Sci. USA, 52: 1121 (1964).PubMedCrossRefGoogle Scholar
  17. 17.
    J. R. Reel and F. T. Kenney, Superinduction of tyrosine aminotransferase in hepatoma cell cultures: differential inhibition of synthesis and turnover by actinomycin D, Proc. Natl. Acad. Sci. USA, 68: 20 (1968).Google Scholar
  18. 18.
    E. B. Thompson, Glucocorticoid induction of tyrosine aminotransferase in cultured cells, in: Glucocorticoid Hormone Action, J. D. Baxter and G. G. Rousseau, eds., Springer-Verlag, Berlin (1979).Google Scholar
  19. 19.
    C. Marcocci, J. L. Cohen and E. F. Grollman, Efeect of actinomycin D on iodide transport in FRTL-5 thyroid cells, Endocrinology, 115: 2123 (1984).PubMedCrossRefGoogle Scholar
  20. 20.
    A.D. Kohn, J. Y. Chan, D. Grieco, V. Nikodem, S. M. Aloj and L. D. Kohn, Thyrotropin increases malic enzyme mRNA levels in rat FRTL-5 thyroid cells, Mol. Endo., 3: in press (1989).Google Scholar
  21. 21.
    S. M. Aloj, D. Grieco, V. M. Nikodem, J. E. Rall and L. D. Kohn, Thyrotropin regulation of malic enzyme in FRTL-5 rat thyroid cells, J. Biol. Chem., submitted (1989).Google Scholar
  22. 22.
    F. Beguinot, S. Formisano, C. M. Rotella, L. D. Kohn and S. M. Aloj, Structural changes caused by thyrotropin in thyroid cells and in liposomes containing reconstituted thyrotropin receptor, Biochem. Biophys. Res. Commun., 110: 48 (1983)PubMedCrossRefGoogle Scholar
  23. 23.
    F. Beguinot, L. Beguinot, D. Tramantano, C. Duilio, S. Formisano, M. Bifulco, F. S. Ambesi-Impiombato and S. M. Aloj, Thyrotropin regulation of membrane fluidity in FRTL-5 thyroid cells, J. Biol. Chem., 262: 1575 (1987).PubMedGoogle Scholar
  24. 24.
    I. Kaneko, Y. Hazama-Shimada and A. Endo, Inhibitory effects on lipid metabolism of cultured cells of ML-2363, a potent inhibitor of HMG CoA reductase, Eur. J. Biochem., 87: 313 (1978).PubMedCrossRefGoogle Scholar
  25. 25.
    M. S. Brown and J. L. Goldstein, Multivalent feedback regulation of HMG CoA reductase: a control mechanism coordinating isoprenoid synthesis and cell growth, J. Lipid Res., 21: 505 (1980).PubMedGoogle Scholar
  26. 26.
    M. D. Siperstein, Role of cholesterogenesis and isoprenoid synthesis in DNA replication and cell growth, J. Lipid Res., 25: 1462 (1984).PubMedGoogle Scholar
  27. 27.
    M. Bifulco, A. Romano, D. Grieco, and S. M. Aloj, TSH regulation of cholesterol mertabolism in thyroid cells: its relation to cell replication, Ann. d’Endocriologie, Masson, Montpelier (1988).Google Scholar
  28. 28.
    L. D. Kohn, Relationships in the structure and function of receptors for glycoprotein hormones, bacterial toxins, and interferon, in: “Receptors and Recognition, Series A,” P. Cuatrecassas and M. F. Greaves, eds., Chapman and Hall, London (1978).Google Scholar
  29. 29.
    P. Laccetti, E. F. Grollman, S. M. Aloj, and L. D. Kohn, Ganglioside dependent return of TSH receptor function in a rat thyroid tumor with a TSH receptor defect, Biochem. Biophys. Res. Commun., 110: 772 (1983).Google Scholar
  30. 30.
    L. D. Kohn, S. M. Aloj, D. Tombaccini D, C. M. Rotella, R. Toccafondi, C. Marcocci, D. Corda and E. F. Grollman, The thyrotropin receptor, in: “Biochemical Actions of Hormones,” G. Litwak, ed., Marcel Dekker, New York (1985).Google Scholar
  31. 31.
    L. M. Brandi, C. M. Rotella, F. D. Ledley, L. D. Kohn and R. Toccafondi, Interactions among TSH, vasointestinal peptide, monoclonal antibodies to the TSH receptor and cholera toxin in normal human thyroid cell cultures, J. Clin. Endocrinol. Moab., 62: 1199 (1986).Google Scholar
  32. 32.
    S. Kosugi, T. Mori, M. Iwamori, Y. Nagai and H. Imura, Islet cell-activating protein reverses antifucosyl GM1 ganglioside antibody-induced inhibition of adenosine 3’,5’-monophosphate production in FRTL-5 rat thyroid cells Endocrinology, 124: 1230 (1989).PubMedCrossRefGoogle Scholar
  33. 33.
    L. D. Kohn, E. Yavin, Z. Yavin, P. Laccetti, P. Vitti, E. F. Grollman and W. A. Valente, Autoimmune thyroid disease studied with monoclonal antibodies to the TSH receptor, in: “Monoclonal Antibodies: Probes for the Study of Autoimmunity and Immunodeficiency,” B. F. Haynes and G. S. Eisenbarth, eds., Academic Press, New York (1983).Google Scholar
  34. 34.
    L. D. Kohn, D. Tombaccini, M. DeLuca, M. Bifulco, E. F. Grollman and W. A. Valente, Monoclonal antibodies and the thyrotropin receptor, in: “ Monoclonal Antibodies to Receptors: Probes for Receptor Structure and Function,” M. F. Greaves, ed., Receptors and Recognition, Series B., 17: 201 (1984).CrossRefGoogle Scholar
  35. 35.
    L. D. Kohn, F. V. Alvarez, C. Marcocci, A. D. Kohn, A. Chen, W. E. Hoffman, D. Tombaccini, W. A. Valente, M. DeLuca, P. Santisteban, and E. F. Grollman, Monoclonal antibody studies defining the origin and properties of Graves’ autoantibodies, Ann. N. Y. Acad. Sci., 475: 157 (1986).PubMedCrossRefGoogle Scholar
  36. 36.
    R. L. Tate, H. I. Schwartz, J. M. Holmes, L. D Kohn and R. J. Winand, TSH receptors in thyroid plasma membranes: characteristics of TSH binding and solubilization of TSH receptor activity by trypsin digestion, J. Biol. Chem., 250: 6509 (1975).PubMedGoogle Scholar
  37. 37.
    R. J. Winand and L. D. Kohn, TSH effects on thyroid cells in culture: effects of trypsin on the TSH receptor and on TSH mediated cAMP changes, J. Biol. Chem., 250: 6534 (1975).PubMedGoogle Scholar
  38. 38.
    L. D. Kohn, W. A. Valente, P. Lacettei, J. Cohen, S. M. Aloj and E. F. Grollman, Multicomponent structure of the thyrotropin receptor: relationships to Graves’ disease, Life Sciences, 32: 15 (1983).PubMedCrossRefGoogle Scholar
  39. 39.
    J. Y. Chan, P. Santisteban, M. DeLuca, O. Isozaki, mE. F. Grollman, and L. D. Kohn, TSH receptor structure, Acta Endocrinologia (Copenh), Suppl. 281, 115: 166 (1987).Google Scholar
  40. 40.
    J. Y. Chan, M. DeLuca, P. Santisteban, O. Isozaki, S. Shifrin, S. M. Aloj, E. F. Grollman, and L. D. Kohn, Nature of thyroid autoantigens: the TSH receptor, in: “Thyroid autoimmunity,” A. Pinchera, S. H. Ingbar and J. M. McKenzie, eds., Plenum Press, New York (1987).Google Scholar
  41. 41.
    J. Y. Chan, M. Lerman, B. S. Prabhakar, O. Isozaki, P. Santisteban, R. C. Kuppers, E. L. Oates, A. L. Notkins and L. D. Kohn, Cloning and characterization of a cDNA that encodes a 70-kDa novel human thyroid autoantigen, J. Biol. Chem., 264: 3651, (1989).PubMedGoogle Scholar
  42. 42.
    L. D. Kohn, O. Isozaki, J. Y. Chan, T. Akamizu, S. Bellur, M. De Luca, P. Santisteban, A. M. Varutti, S. Grimaz, S. Ikuyama, M. Saji, and G. Owens, The thyrotropin receptor in FRTL-5 thyroid cells: a cloning approach, in: “FRTL-5 Today,” H. Perrild and F. S. Ambesi-Impiombato, eds., Elsevier Medical Sciences, Amsterdam (1989).Google Scholar
  43. 43.
    B. R. Mullin, G. Lee, F. D. Ledley, R. J. Winand and L. D. Kohn, Thyrotropin interactions with human fat cell membrane preparations and the finding of a soluble TSH binding component, Biochem. Biophys. Res. Commun., 69: 55 (1976).Google Scholar
  44. 44.
    F. Pekonen and B. D. Weintraub, Thyrotropin binding to cultured lymphocytes and thyroid cells, Endocrinology, 103: 1668 (1978).Google Scholar
  45. 45.
    M. Kozak, An analysis of 5’-noncoding sequences from 699 vertebrate mRNAs, Nucleic Acids Res. 15: 8125 (1987).PubMedCrossRefGoogle Scholar
  46. 46.
    W. A. Valente, P. Vitti, Z. Yavin, E. Yavin, C. M. Rotella, E. F. Grollman, R. S. Toccafondi and L. D. Kohn, Monoclonal antibodies to the thyrotropin receptor: the identification of blocking a n d stimulating antibodies, Proc. Natl. Acad. Sci. USA, 79: 6680 (1982).PubMedCrossRefGoogle Scholar
  47. 47.
    W. A. Valente, P. Vitti, C. M. Rotella, M. M. Vaughan, S. M. Aloj, E. F. Grollman, F. S. AmbesiImpiombato and L. D. Kohn, Antibodies that pmnote thyroid growth: a distinct population of thyroid- stimulating autoantibodies, N. Engl.J.Med., 309: 1028 (1983).PubMedCrossRefGoogle Scholar
  48. 48.
    E. F. Grollman, G. Lee, F. S. Ambesi-Impiombato, M. F. Meldolesi, S. M. Aloj, H. G. Coon, H. R. Kaback and L. D. Kohn, Effects of thyrotropin on thyroid cell membrane: hyperpolarization induced by hormone-receptor interaction, Proc. Natl. Acad. Sci. USA, 74: 2352 (1977).PubMedCrossRefGoogle Scholar
  49. 49.
    L. Bartalena, G. Fenzi, P. Vitti, D. Tombaccini, A. Antonelli, E. Macchia, L. Chiovato, L. D. Kohn and A. Pinchera, Interaction of the TSH receptor of rat FRTL-5 thyroid cells with TSH and a thyrotropin-stimulating autoantibody from Graves’ patients, Biochem. Biophys. Res. Commun., 143: 266 (1986).CrossRefGoogle Scholar
  50. 50.
    B. C. Kress and R. G. Spiro, Studies on the glycoprotein nature of the thyrotropin receptor: interaction with lectins and purification of the bovine protein with the use of Bandeiraca (Griffonia) simplicifolia I affinity chromatography, Endocrinology_, 118: 974 (1986).PubMedCrossRefGoogle Scholar
  51. 51.
    G. P. Allaway, B. S. Prabhakar, A. A. Vivino, J. Y. Chan, L. D. Kohn and A. L. Notkins, Characterization of a novel 70 kilodalton thyroid autoantigen produced in the baculovirus expression system. [Abstract], Proceedings 23rd Annual Meeting European Society for Clinical Investigation, Elsevier, Amsterdam (1989).Google Scholar
  52. 52.
    L. D. Kohn, O. Isozaki, J. Y. Chan, T. Akamizu, S. Bellur, P. Santisteban, S. Ikuyama, M. Saji, S. Doi, K. Tahara, S. Kosugi, H. Sabe, and T. Mori, Characterization of the thyrotropin receptor and other Graves’ disease autoantigens, in: “Proceedings International Symposium on Glycoprotein Hormones,” W. Chin, ed., Plenum Publishing Corp. New York (1989).Google Scholar
  53. 53.
    J. Y. Chan, M. Lerman, W. O. McBride, P. Santisteban, O. Isozaki, A. L. Notkins and L. D. Kohn, Isolation, characterization, and chromosomal localization of a cDNA clone of an autoantigen in Graves’ disease also identified by antibodies to the TSH receptor. [Abstract] 62nd Meeting American Thyroid Association, Endocrinology, 120 (Supplement): T16 (1987).Google Scholar
  54. 54.
    J. Y. Chan, P. Santisteban, C. Kozak, R. C. Kuppers and L.D. Kohn, Genomic organization and chromosomal mapping of a mouse lymphocyte gene: its cDNA sequence is homologous to a thyroid autoantigen. [Abstract] 63rd Meeting American Thyroid Association, Endocrinology, 121 (Supplement): T52 (1988).Google Scholar
  55. 55.
    P. Kendall-Taylor, A. Stephenson, A. Stratton, S. S. Papiha, P. Perros and D. F. Roberts, Differentiation of autoimmune opthalmopathy from Graves’ hyperthyroidism by analysis of genetic markers. Clinical Endocrinology, 28: 601 (1988).PubMedGoogle Scholar
  56. 56.
    C. M. Rotella, R. Zonefrate, R. Toccafondi, W. A. Valente, and L. D. Kohn, Ability of monoclonal antibodies to the TSH receptor to increase collagen synthesis in human fibroblasts, an assay which appears to measure exophthalmogenic immunoglobulins in Graves’ sera, J. Clin. Endocrinol. Metab. 62: 357 (1986).PubMedCrossRefGoogle Scholar
  57. 57.
    D. Corda, R. D. Sekura and L. D. Kohn, Thyrotropin effect on the availability of Ni Regulatory protein in FRTL-5 thyroid cells to ADPribosylation by pertussis toxin, Eur. J. Biochem., 166: 475 (1987).PubMedCrossRefGoogle Scholar
  58. 58.
    F. Riberio-Neto, L. Birnbaumer and J. B. Field, Incubation of bovine thyroid slices with TSH is associated with a decrease in the ability of pertussis toxin to ADPribosylate guanine nucleotide regulatory components, Mol. Endo., 1: 482, (1987).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1989

Authors and Affiliations

  • Leonard D. Kohn
    • 1
  • Motoyasu Saji
    • 1
  • Takashi Akamizu
    • 1
  • Shoichiro Ikuyama
    • 1
  • Osamu Isozaki
    • 1
  • Aimee D. Kohn
    • 1
  • Pilar Santisteban
    • 1
  • John Y. Chan
    • 1
  • Shashikumar Bellur
    • 1
  • Carlo M. Rotella
    • 1
  • Francisco V. Alvarez
    • 1
  • Salvatore M. Aloj
    • 1
  1. 1.Section on Cell Regulation Laboratory of Biochemistry and Metabolism National Institute of Diabetes, Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA

Personalised recommendations