Thyrotropin receptors

Paschke R, Ludgate M (1997) The thyrotropin receptor in thyroid diseases. N Engl J Med 337 1675-1681... 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

On the other hand, some receptors are truly promiscuous in that they can activate two or more G-proteins from quite different classes, even in their normal cellular environment. For example, similar concentrations of thyroid-stimulating hormone (TSH 0.1-100 U/ml) can stimulate the incorporation of 32P-GTP into a, aQ, a12, a13, as, and aq/11 through activation of the thyrotropin receptor in membranes from human thyroid gland. TRH activation of Ca2+ currents in GH3 cells is obtunded equally by antisense-depletion of l2, aa, and aq/11, but not of aQ. Some individual genotypic P2y nucleotide receptors can also couple with equal affinity to PTx-sensitive and PTx-insensitive G-proteins in sympathetic neurons. The degree, or otherwise, of such promiscuity is presumably determined by the structure of the receptor protein itself. 

Wonerow, R, Neumann, S., Gudermann, T., and Paschke, R. 2001. Thyrotropin receptor mutations as a tool to understand thyrotropin receptor action. Journal of Molecular Medicine 79(12), 707-721. 

In Graves disease, hyperthyroidism results from the action of thyroid-stimulating antibodies (TSAb) directed against the thyrotropin receptor on the surface of the thyroid cell. These immunoglobulin G antibodies bind to the receptor and activate the enzyme adenylate cyclase in the same manner as TSH. 

Chazenbalk, G. D Kakinuma, A., Jaume, J. C., McLachlan, S. M., and Rapoport, B. (1996) Evidence for negative cooperativity among human thyrotropin receptors overexpressed in mammalian cells. Endocrinology 137,4586-4591. 

Duprez, L., Parma, J., Vansande, J., et al. (1994) Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal-dominant hyperthyroidism. Nat. Genet. 7, 396 01. 

Jordan, N., WiUiams, N., Gregory, J. W., Evans, C., Owen, M., and 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, 1002-1005. 

Tonacchera, M., Agretti, P., Chiovato, L., et al. (2000) Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter. J. Clin. Endocrinol. Metab. 85, 2270-2274. 

Pohlenz, J., Pfarr, N., Kruger, S., and Hesse, V. (2006) SubcUnical hyperthyroidism due to a thyrotropin receptor (TSHR) gene mutation (S505R). Acta Paediatr. 95, 1685-1687. 

Kaczur, V., Puskas, L. G., Takacs, M., et al. (2003) Evolution of the thyrotropin receptor a G protein coupled receptor with an intrinsic capacity to dimerize. Mol. Genet. Metab. 78, 275-290. 

Rossi M, Dimida A, Dell anno MT, Trincavelli ML, Agretti P, Giorgi F et al (2007) The thyroid disrupter l,l,l-trichloro-2,2-bis(p-chloropheyl)ethane appears to be an uncompetitive inverse agonist for the thyrotropin receptor. J Pharmacol Exp Ther 320 465 74... 

Burch, H. B., Nagy, E. V., Kain, K. C, Lanar, D E, Carr, F. E., Wartofsky, L., and Burman, K D (1993) Expression polymerase chain reaction for the in vitro synthesis and epitope mapping of autoantigen. Application to the human thyrotropin receptor J Immunol Methods 158, 123-130... 

Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Stimulation of adipogenesis, peroxisome proliferator-acti-vated receptor-gamma (PPARv) and thyrotropin receptor by PPARv agonists in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab 2002 87 2352-2358. 

Nine of 27 patients with multiple sclerosis developed antibodies against the thyrotropin receptor and carbima-zole-responsive autoimmune hyperthyroidism after a 5-day pulse of alemtuzumab, a finding that was not reported in patients treated for other disorders (18). 

It was presumed that the iodine load (about 30 g) had precipitated thyrotoxicosis in this patient, who had antibodies to the thyrotropin receptor, which in turn precipitated collapse due to adrenal insufficiency. 

A variation of the pharmacophore library was seen in an approach used to determine CD4+ T cell epitopes.31 In a 14-mer peptide, the researchers keep residues in positions 1, 4, and 6 constant since they functioned as anchor positions for binding receptor, and proceeded to vary the other residues in the peptide. This allowed the use of a shorter synthetic route compared to one that would be needed if all positions were to be varied. Limiting the size of the library allowed the authors to obtain better assays. By doing a partial release of the peptides, the authors were able to find the final peptide that represented the epitope of the T cell receptor. In another example, the epitope to inhibit stimulation of the thyrotropin receptor also was found via combinatorial libraries.32 Since the synthesis of a totally random hexapeptide library was deemed impractical, the authors opted to hold one position constant while the other five residues were randomized. This method was repeated for each residue in the peptide. The residues that were determined to be the most active were used as a basis for a second-generation library. The only limitation of the library was not the quantity of product synthesized, but to properly pinpoint the peptides in an assay. 

Ando T, Latif R, Davies TF. Thyrotropin receptor antibodies new insights into their actions and clinical relevance. Best Pract Res Clin Endocrinol Metab. 2005 19 33-52. 

Schott M, Scherbaum WA, Morgenthaler NG. Thyrotropin receptor autoantibodies in Graves disease. Trends Endocrinol Metab. 2005 16 243-248. 

Bockmann J, Winter C, Wittkowski W, Kreutz MR, Bockers TM (1997) Cloning and expression of a brain-derived TSH receptor. Biochem Biophys Res Commun 238 173-1780 Castagiola A, Swillens S, Niccoli P, Dumont JE, Vassart G, Ludgate M (1992) Binding assay for thyrotropin receptor autoantibodies using the recombinant receptor protein. J Clin Endocrinol Metab 75 1540-1544 Cole ES, Lee K, Lauziere K et al. (1993) Recombinant human thyroid stimulating hormone development of a biotech-... 

Vassart G, Dumont JE (1992) The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 13 569-611... 

As stated, Graves ophthalmopathy worsens in many patients despite antithyroid therapy, especially in therapies that cause rapid alteration in thyroid tissue and function. More recent studies suggested that, as compared with other forms of antithyroid therapy, 1 is more likely to be followed by the development or exacerbation of Graves ophthalmopathy. This may reflect only the increase in thyrotropin-receptor antibody and other thyroid antibodies in serum after destruction of the thyroid gland by RAI. Consideration should be given to initiating oral steroid therapy before 1 therapy. 

Govaerts C, Lefort A, Costagliola S, et al. A conserved Asn in transmembrane helix 7 is an on/off switch in the activation of the thyrotropin receptor. J Biol Chem... 

Latif R, Ando T, Daniel S, Davies TF. Localization and regulation of thyrotropin receptors within lipid rafts. Endocrinology 2003 144 4725-4728. 

Brown R, Kertiles L, Kleinmann R. Choice of immunoglobin G purification method in assays for antibodies to the thyrotropin receptor. Clin Chem 1986 32 2034-9. 

Cho BY, Shong MH, Yi KH, Lee HK, Koh CS, Min HK, Evaluation of serum basal thyrotropin levels and thyrotropin receptor antibody levels and thyrotropin receptor antibody activities as prognostic markers for discontinuation of antithyroid drug treatment in patients with Graves disease. Clin Endocrinol 1992 36 585-90. 

Feldt-Rasmussen U. Analytical and clinical performance goals for testing autoantibodies to thyroperox-idase, thyroglobulin, and thyrotropin receptor. Clin Chem 1996 42 160-3. 

Feldt-Rasmussen U, Schleusener H> Carayon P. Metaanalysis evaluation of the impact of thyrotropin receptor antibodies on long term remission after medical therapy of Graves disease. J Clin Endocrinol Metab 1994 78 98-102. 

Massart C, Hody B, Mouchel L, Edan G, Nicol M. Assays for thyrotropin-receptor binding and thyroid-stimulating antibodies in sera from patients with Graves disease. CUn Chem 1986 32 1332-5,... 

Morris JC 3rd, Hay ID, Nelson RE, Jiang NS. Clinical utility of thyrotropin-receptor antibody assays Comparison of radioreceptor and bioassay methods. Mayo Clin Proc 1988 63 707-17. 

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