Molecular mechanisms of thyroid-stimulating hormone receptor regulation – from signaling to drug development

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

The thyroid stimulating hormone (TSH) receptor, which specifically binds TSH and thyrostimulin, is a key component of the thyroid system that controls a wide range of vital processes in humans and vertebrates. This receptor is structurally similar to gonadotropin receptors. It also has a large ectodomain with an orthosteric site for hormone binding, a transmembrane domain that interacts with heterotrimeric G proteins and β-arrestins and in the internal cavity of which allosteric sites are localized, and is also capable of forming functionally active homodi(oligo)meric complexes. In pathology, antibodies with different profiles of biological activity are produced against the extracellular regions of the TSH receptor, causing autoimmune diseases of the thyroid gland. The efficiency of TSH interaction with the orthosteric site and the selectivity of stimulation of a certain intracellular cascade are controlled by a number of allosteric mechanisms and regulators, including the N-glycosylation status of TSH molecules, complex formation of the TSH receptor, localization of the “internal” agonist in its hinge loop, and the lipid composition of the membrane. This review is devoted to the mechanisms of orthosteric and allosteric regulation of TSH receptor activity, their relationships, as well as the role of changes in TSH receptor activity in the development of autoimmune diseases and thyroid cancer, Graves' ophthalmopathy, and osteoporosis. It also considers achievements in the development of low-molecular allosteric regulators of the TSH receptor and the prospects for their possible use in medicine.

About the authors

A. O. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: alex_shpakov@list.ru
Deputy Director, Head of Laboratory, Doctor of Biological Sciences St. Petersburg, 194223

K. V. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: derkatch_k@list.ru
Leading Researcher, PhD St. Petersburg, 194223

References

  1. Shpakov A.O., Derkach K.V. Multiple mechanisms of allosteric regulation of the luteinizing hormone receptor. Uspekhi fiziologicheskikh nauk. Sci. 2024. Vol. 53. No. 4. pp. 45–74. (In Russ.) https://doi.org/10.31857/S0301179824040031
  2. Agwuegbo U.T., Colley E., Albert A.P. et al. Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling. Front. Endocrinol. (Lausanne). 2021. Vol. 12. 765727. https://doi.org/10.3389/fendo.2021.765727
  3. Allen M.D., Neumann S., Gershengorn M.C. Occupancy of both sites on the thyrotropin (TSH) receptor dimer is necessary for phosphoinositide signaling. FASEB J. 2011. Vol. 25. No. 10. P. 3687–3694. https://doi.org/10.1096/fj.11-188961
  4. Allen M.D., Neumann S., Gershengorn M.C. Small-molecule thyrotropin receptor agonist activates naturally occurring thyrotropin-insensitive mutants and reveals their distinct cyclic adenosine monophosphate signal persistence. Thyroid. 2011. Vol. 21. No. 8. P. 907–912. https://doi.org/10.1089/thy.2011.0025
  5. Ashim J., Seo M.J., Ji S., Heo J., Yu W. Research approaches for exploring the hidden conversations of G protein-coupled receptor transactivation. Mol. Pharmacol. 2025. Vol. 107. No. 6. 100043. https://doi.org/10.1016/j.molpha.2025.100043
  6. Bahn R.S. Thyrotropin receptor expression in orbital adipose/connective tissues from patients with thyroid-associated ophthalmopathy. Thyroid. 2002. Vol. 12. No. 3. P. 193–195. https://doi.org/10.1089/105072502753600124
  7. Bakhtyukov A.A., Derkach K.V., Fokina E.A. et al. Development of Low-Molecular-Weight Allosteric Agonist of Thyroid-Stimulating Hormone Receptor with Thyroidogenic Activity. Dokl. Biochem. Biophys. 2022. Vol. 503. No. 1. P. 67–70. https://doi.org/10.1134/S1607672922020016
  8. Bock A., Bermudez M. Allosteric coupling and biased agonism in G protein-coupled receptors. FEBS J. 2021. V. 288. No. 8. P. 2513–2528. https://doi.org/10.1111/febs.15783
  9. Boutin A., Eliseeva E., Gershengorn M.C., Neumann S. β-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation. FASEB J. 2014. Vol. 28. No. 8. P. 3446–3455. https://doi.org/10.1096/fj.14-251124
  10. Boutin A., Gershengorn M.C., Neumann S. β-Arrestin 1 in Thyrotropin Receptor Signaling in Bone: Studies in Osteoblast-Like Cells. Front. Endocrinol. (Lausanne). 2020. Vol. 11. P. 312. https://doi.org/10.3389/fendo.2020.00312
  11. Boutin A., Krieger C.C., Marcus-Samuels B. et al. TSH Receptor Homodimerization in Regulation of cAMP Production in Human Thyrocytes in vitro. Front. Endocrinol. (Lausanne). 2020. Vol. 11. P. 276. https://doi.org/10.3389/fendo.2020.00276
  12. Bruno R., Ferretti E., Tosi E. et al. Modulation of thyroid-specific gene expression in normal and nodular human thyroid tissues from adults: an in vivo effect of thyrotropin. J. Clin. Endocrinol. Metab. 2005. Vol. 90. No. 10. P. 5692–5697. https://doi.org/10.1210/jc.2005-0800
  13. Brüser A., Schulz A., Rothemund S. et al. The Activation Mechanism of Glycoprotein Hormone Receptors with Implications in the Cause and Therapy of Endocrine Diseases. J. Biol. Chem. 2016. Vol. 291. No. 2. P. 508–520. https://doi.org/10.1074/jbc.M115.701102
  14. Castro I., Lima L., Seoane R., Lado-Abeal J. Identification and functional characterization of two novel activating thyrotropin receptor mutants in toxic thyroid follicular adenomas. Thyroid. 2009. Vol. 19. No. 6. P. 645–649. https://doi.org/10.1089/thy.2009.0002
  15. Chu Y.D., Yeh C.T. The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells. Cells. 2020. Vol. 9. No. 7. P. 1730. https://doi.org/10.3390/cells9071730
  16. Claeysen S., Govaerts C., Lefort A. et al. A conserved Asn in TM7 of the thyrotropin receptor is a common requirement for activation by both mutations and its natural agonist. FEBS Lett. 2002. Vol. 517. No. 1–3. P. 195–200. https://doi.org/10.1016/s0014-5793(02)02620-0
  17. Contreras-Jurado C. Thyroid Hormones and Co-workers: An Overview. Methods Mol. Biol. 2025. Vol. 2876. P. 3–16. https://doi.org/10.1007/978-1-0716-4252-8_1
  18. Costagliola S., Panneels V., Bonomi M. et al. Tyrosine sulfation is required for agonist recognition by glycoprotein hormone receptors. EMBO J. 2002. Vol. 21. No. 4. P. 504–513. https://doi.org/10.1093/emboj/21.4.504
  19. Couët J., de Bernard S., Loosfelt H. et al. Cell surface protein disulfide-isomerase is involved in the shedding of human thyrotropin receptor ectodomain. Biochemistry. 1996. Vol. 35. No. 47. P. 14800–14805. https://doi.org/10.1021/bi961359w
  20. Cui X., Wang F., Liu C. A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy. Front. Immunol. 2023. Vol. 14. 1062045. https://doi.org/10.3389/fimmu.2023.1062045
  21. Dardente H., Migaud M. Thyroid hormone and hypothalamic stem cells in seasonal functions. Vitam. Horm. 2021. Vol. 116. P. 91–131. https://doi.org/10.1016/bs.vh.2021.02.005
  22. De Gregorio F., Pellegrino M., Picchietti S. et al. The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT) alters the membrane raft location of the TSH receptor stably expressed in Chinese hamster ovary cells. Toxicol. Appl. Pharmacol. 2011. Vol. 253. No. 2. P. 121–129. https://doi.org/10.1016/j.taap.2011.03.018
  23. Derkach K.V., Bakhtyukov A.A., Sorokoumov V.N. et al. Low Molecular Weight Thyrotropin Receptor Inverse Agonist is Active upon both Intraperitoneal and Oral Administration. J. Evol. Biochem. Physiol. 2024. Vol. 60. No. 1. P. 295–305. https://doi.org/10.1134/S0022093024010216
  24. Derkach K.V., Bakhtyukov A.A., Sorokoumov V.N., Shpakov A.O. New Thieno-[2,3-d]pyrimidine-Based Functional Antagonist for the Receptor of Thyroid Stimulating Hormone. Dokl. Biochem. Biophys. 2020. Vol. 491. No. 1. P. 77–80. https://doi.org/10.1134/S1607672920020064
  25. Derkach K.V., Didenko E.A., Sorokoumov V.N., Shpakov A.O. Substitution of an Ethyl Group with a Methyl Group in the Variable Moiety of TPY3m, a Thyroid-Stimulating Hormone Receptor Agonist, Modifies the Effect of This Analogue on the Basal and Thyroliberin-Stimulated Levels of Thyroid Hormones in Rats. Cell Tissue Biol. 2025. Vol. 19. No. 2. P. 102–112. https://doi.org/10.1134/S1990519X24600716
  26. Derkach K.V., Didenko E.A., Sorokoumov V.N., Zakharova I.O., Shpakov A.O. Low-molecular-weight Ligand of the Thyroid-stimulating Hormone Receptor with the Activity of a Partial Agonist and a Negative Allosteric Modulator. Dokl. Biochem. Biophys. 2025. Vol. 520. No. 1. P. 53–57. https://doi.org/10.1134/S1607672924600799
  27. Derkach K.V., Fokina E.A., Bakhtyukov A.A. et al. The Study of Biological Activity of a New Thieno[2,3-D]-Pyrimidine-Based Neutral Antagonist of Thyrotropin Receptor. Bull. Exp. Biol. Med. 2022. Vol. 172. No. 6. P. 713–717. https://doi.org/10.1007/s10517-022-05462-x
  28. Derkach K.V., Pechalnova A.S., Nazarov I.R. et al. Development of Thieno[2,3-d]-pyrimidine-based Positive Allosteric Modulators of Thyroid Stimulating Hormone Receptor and their Effect on Thyroid Status in Rats. J. Evol. Biochem. Physiol. 2025. Vol. 61. No. 2. P. 425–437. https://doi.org/10.1134/S002209302502005X
  29. Derkach K.V., Pechalnova A.S., Sorokoumov V.N. et al. Effect of a Low-Molecular-Weight Allosteric Agonist of the Thyroid-Stimulating Hormone Receptor on Basal and Thyroliberin-Stimulated Activity of Thyroid System in Diabetic Rats. Int. J. Mol. Sci. 2025. Vol. 26. No. 2. P. 703. https://doi.org/10.3390/ijms26020703
  30. Derkach K.V., Sorokoumov V.N., Morina I.Y. et al. Regulatory Effects of 5-Day Oral and Intraperitoneal Administration of a Thienopyrimidine Derivative on the Thyroid Status in Rats. Bull. Exp. Biol. Med. 2024. Vol. 177. No. 4. P. 559–563. https://doi.org/10.1007/s10517-024-06223-8
  31. Draman M.S., Zhang L., Dayan C., Ludgate M. Orbital Signaling in Graves' Orbitopathy. Front. Endocrinol. (Lausanne). 2021. Vol. 12. 739994. https://doi.org/10.3389/fendo.2021.739994
  32. Duan J., Xu P., Cheng X. et al. Structures of full-length glycoprotein hormone receptor signalling complexes. Nature. 2021. Vol. 598. No. 7882. P. 688–692. https://doi.org/10.1038/s41586-021-03924-2
  33. Duan J., Xu P., Luan X. et al. Hormone- and antibody-mediated activation of the thyrotropin receptor. Nature. 2022. Vol. 609. No. 7928. P. 854–859. https://doi.org/10.1038/s41586-022-05173-3
  34. Ebrhim R.S., Bruellman R.J., Watanabe Y. et al. Central Congenital Hypothyroidism Caused by a Novel Mutation, C47W, in the Cysteine Knot Region of TSHβ. Horm. Res. Paediatr. 2019. Vol. 92. No. 6. P. 390–394. https://doi.org/10.1159/000504981
  35. Estrada J.M., Soldin D., Buckey T.M., Burman K.D., Soldin O.P. Thyrotropin isoforms: implications for thyrotropin analysis and clinical practice. Thyroid. 2014. Vol. 24. No. 3. P. 411–423. https://doi.org/10.1089/thy.2013.0119
  36. Evans M., Sanders J., Tagami T. et al. Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample. Clin. Endocrinol. (Oxf.). 2010. Vol. 73. No. 3. P. 404–412. https://doi.org/10.1111/j.1365-2265.2010.03831.x
  37. Fan Q.R., Hendrickson W.A. Structural biology of glycoprotein hormones and their receptors. Endocrine. 2005. V. 26. No. 3. P. 179–188. https://doi.org/10.1385/endo:26:3:179
  38. Faust B., Billesbølle C.B., Suomivuori C.M. et al. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature. 2022. Vol. 609. No. 7928. P. 846–853. https://doi.org/10.1038/s41586-022-05159-1
  39. Feldt-Rasmussen U., Effraimidis G., Klose M. The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions. Mol. Cell. Endocrinol. 2021. Vol. 525. 111173. https://doi.org/10.1016/j.mce.2021.111173
  40. Ferraz C., Paschke R. Inheritable and sporadic non-autoimmune hyperthyroidism. Best Pract. Res. Clin. Endocrinol. Metab. 2017. Vol. 31. No. 2. P. 265–275. https://doi.org/10.1016/j.beem.2017.04.005
  41. Fröhlich E., Wahl R. Pars Distalis and Pars Tuberalis Thyroid-Stimulating Hormones and Their Roles in Macro-Thyroid-Stimulating Hormone Formation. Int. J. Mol. Sci. 2023. Vol. 24. No. 14. 11699. https://doi.org/10.3390/ijms241411699
  42. Furmaniak J., Sanders J., Núñez Miguel R., Rees Smith B. Mechanisms of Action of TSHR Autoantibodies. Horm. Metab. Res. 2015. Vol. 47. No. 10. P. 735–752. https://doi.org/10.1055/s-0035-1559648
  43. Furmaniak J., Sanders J., Sanders P., Li Y., Rees Smith B. TSH receptor specific monoclonal autoantibody K1-70TM targeting of the TSH receptor in subjects with Graves' disease and Graves' orbitopathy-Results from a phase I clinical trial. Clin. Endocrinol. (Oxf.). 2022. Vol. 96. No. 6. P. 878–887. https://doi.org/10.1111/cen.14681
  44. Girnita L., Janssen J.A.M.J.L., Smith T.J. G-protein coupled & membrane tyrosine kinase receptors relationship yield therapy opportunities. Endocr. Rev. 2025. bnaf019. https://doi.org/10.1210/endrev/bnaf019
  45. Gluvic Z., Obradovic M., Stewart A.J. et al. Levothyroxine Treatment and the Risk of Cardiac Arrhythmias – Focus on the Patient Submitted to Thyroid Surgery. Front. Endocrinol. (Lausanne). 2021. Vol. 12. 758043. https://doi.org/10.3389/fendo.2021.758043
  46. Godbole A., Lyga S., Lohse M.J., Calebiro D. Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription. Nat. Commun. 2017. Vol. 8. No. 1. P. 443. https://doi.org/10.1038/s41467-017-00357-2
  47. Grasberger H., Refetoff S. Resistance to thyrotropin. Best Pract. Res. Clin. Endocrinol. Metab. 2017. Vol. 31. No. 2. P. 183–194. https://doi.org/10.1016/j.beem.2017.03.004
  48. He X., Duan J., Ji Y. et al. Hinge region mediates signal transmission of luteinizing hormone and chorionic gonadotropin receptor. Comput. Struct. Biotechnol. J. 2022. Vol. 20. P. 6503–6511. https://doi.org/10.1016/j.csbj.2022.11.039
  49. Hoyer I., Haas A.K., Kreuchwig A., Schülein R., Krause G. Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists. Biochem. Soc. Trans. 2013. Vol. 41. No. 1. P. 213–217. https://doi.org/10.1042/BST20120319
  50. Hsu S.Y., Nakabayashi K., Bhalla A. Evolution of glycoprotein hormone subunit genes in bilateral metazoa: identification of two novel human glycoprotein hormone subunit family genes, GPA2 and GPB5. Mol. Endocrinol. 2002. Vol. 16. No. 7. P. 1538–1551. https://doi.org/10.1210/mend.16.7.0871
  51. Jang D., Morgan S.J., Klubo-Gwiezdzinska J. et al. Thyrotropin, but Not Thyroid-Stimulating Antibodies, Induces Biphasic Regulation of Gene Expression in Human Thyrocytes. Thyroid. 2020. Vol. 30. No. 2. P. 270–276. https://doi.org/10.1089/thy.2019.0418
  52. Jin M., Jang A., Kim C.A. et al. Long-term follow-up result of antithyroid drug treatment of Graves' hyperthyroidism in a large cohort. Eur. Thyroid J. 2023. Vol. 12. No. 2. :e220226. https://doi.org/10.1530/ETJ-22-0226
  53. Kleinau G., Haas A.K., Neumann S. et al. Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor. FASEB J. 2010. Vol. 24. No. 7. P. 2347–2354. https://doi.org/10.1096/fj.09-149146
  54. Kleinau G., Worth C.L., Kreuchwig A. et al. Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work. Front. Endocrinol. (Lausanne). 2017. Vol. 8. P. 86. https://doi.org/10.3389/fendo.2017.00086
  55. Krause G., Eckstein A., Schülein R. Modulating TSH Receptor Signaling for Therapeutic Benefit. Eur. Thyroid J. 2020. Vol. 9. Suppl. 1. P. 66–77. https://doi.org/10.1159/000511871
  56. Krause G., Kreuchwig A., Kleinau G. Extended and structurally supported insights into extracellular hormone binding, signal transduction and organization of the thyrotropin receptor. PLoS One. 2012. Vol. 7. No. 12. e52920. https://doi.org/10.1371/journal.pone.0052920
  57. Krause G., Marcinkowski P. Intervention Strategies into Glycoprotein Hormone Receptors for Modulating (Mal-)function, with Special Emphasis on the TSH Receptor. Horm. Metab. Res. 2018. Vol. 50. No. 12. P. 894–907. https://doi.org/10.1055/a-0749-6528
  58. Kreuchwig A., Kleinau G., Krause G. Research resource: novel structural insights bridge gaps in glycoprotein hormone receptor analyses. Mol. Endocrinol. 2013. Vol. 27. No. 8. P. 1357–1363. https://doi.org/10.1210/me.2013-1115
  59. Krieger C.C., Neumann S., Gershengorn M.C. Is There Evidence for IGF1R-Stimulating Abs in Graves' Orbitopathy Pathogenesis?. Int. J. Mol. Sci. 2020. Vol. 21. No. 18. 6561. https://doi.org/10.3390/ijms21186561
  60. Kushnir J., Gumpper R.H. Molecular Glues: A New Approach to Modulating GPCR Signaling Bias. Biochemistry. 2025. Vol. 64. No. 4. P. 749–759. https://doi.org/10.1021/acs.biochem.4c00734
  61. Lanzolla G., Marinò M., Menconi F. Graves disease: latest understanding of pathogenesis and treatment options. Nat. Rev. Endocrinol. 2024. Vol. 20. No. 11. P. 647–660. https://doi.org/10.1038/s41574-024-01016-5
  62. Latif R., Ali M.R., Ma R. et al. New small molecule agonists to the thyrotropin receptor. Thyroid. 2015. Vol. 25. No. 1. P. 51–62. https://doi.org/10.1089/thy.2014.0119
  63. Latif R., Mezei M., Davies T.F. Mechanisms in Thyroid Eye Disease: The TSH Receptor Interacts Directly With the IGF-1 Receptor. Endocrinology. 2025. Vol. 166. No. 2. bqaf009. https://doi.org/10.1210/endocr/bqaf009
  64. Latif R., Morshed S.A., Ma R. et al. A Gq Biased Small Molecule Active at the TSH Receptor. Front. Endocrinol. (Lausanne). 2020. Vol. 11. P. 372. https://doi.org/10.3389/fendo.2020.00372
  65. Laugwitz K.L., Allgeier A., Offermanns S. et al. The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. Proc. Natl. Acad. Sci. U S A. 1996. Vol. 93. No. 1. P. 116–120. https://doi.org/10.1073/pnas.93.1.116
  66. Lazim R., Suh D., Lee J.W. et al. Structural Characterization of Receptor-Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers. Int. J. Mol. Sci. 2021. Vol. 22. No. 6. 3241. https://doi.org/10.3390/ijms22063241
  67. Lazzaretti C., Paradiso E., Sperduti S. et al. Trafficking of luteinizing hormone receptor directs the differential signal activation between luteinizing hormone and chorionic gonadotropin. Int. J. Biol. Macromol. 2025. Vol. 318. Pt. 3. 145247. https://doi.org/10.1016/j.ijbiomac.2025.145247
  68. Lin H.H. An Alternative Mode of GPCR Transactivation: Activation of GPCRs by Adhesion GPCRs. Int. J. Mol. Sci. 2025. Vol. 26. No. 2. P. 552. https://doi.org/10.3390/ijms26020552
  69. Madsen J.J., Ye L., Frimurer T.M., Olsen O.H. Mechanistic basis of GPCR activation explored by ensemble refinement of crystallographic structures. Protein Sci. 2022. Vol. 31. No. 11. e4456. https://doi.org/10.1002/pro.4456
  70. Marcinkowski P., Hoyer I., Specker E. et al. A New Highly Thyrotropin Receptor-Selective Small-Molecule Antagonist with Potential for the Treatment of Graves' Orbitopathy. Thyroid. 2019. Vol. 29. No. 1. P. 111–123. https://doi.org/10.1089/thy.2018.0349
  71. Mendonça-Reis E., Guimarães-Nobre C.C., Teixeira-Alves L.R., Miranda-Alves L., Berto-Junior C. TSH Receptor Reduces Hemoglobin S Polymerization and Increases Deformability and Adhesion of Sickle Erythrocytes. Anemia. 2024. Vol. 2024. 7924015. https://doi.org/10.1155/2024/7924015
  72. Mezei M., Latif R., Davies T.F. Modeling TSH Receptor Dimerization at the Transmembrane Domain. Endocrinology. 2022. Vol. 163. No. 12. bqac168. https://doi.org/10.1210/endocr/bqac168
  73. Michalek K., Morshed S.A., Latif R., Davies T.F. TSH receptor autoantibodies. Autoimmun. Rev. 2009. Vol. 9. No. 2. P. 113–116. https://doi.org/10.1016/j.autrev.2009.03.012
  74. Mirchandani-Duque M., Choucri M., Hernández-Mondragón J.C. et al. Membrane Heteroreceptor Complexes as Second-Order Protein Modulators: A Novel Integrative Mechanism through Allosteric Receptor-Receptor Interactions. Membranes (Basel). 2024. Vol. 14. No. 5. P. 96. https://doi.org/10.3390/membranes14050096
  75. Morshed S.A., Davies T.F. Graves' Disease Mechanisms: The Role of Stimulating, Blocking, and Cleavage Region TSH Receptor Antibodies. Horm. Metab. Res. 2015. Vol. 47. No. 10. P. 727–734. https://doi.org/10.1055/s-0035-1559633
  76. Mueller S., Kleinau G., Szkudlinski M.W. et al. The superagonistic activity of bovine thyroid-stimulating hormone (TSH) and the human TR1401 TSH analog is determined by specific amino acids in the hinge region of the human TSH receptor. J. Biol. Chem. 2009. Vol. 284. No. 24. P. 16317–16324. https://doi.org/10.1074/jbc.M109.005710
  77. Nagayama Y., Nishihara E. Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases. Endocr. J. 2022. Vol. 69. No. 11. P. 1285–1293. https://doi.org/10.1507/endocrj.EJ22-0391
  78. Neumann S., Eliseeva E., Boutin A. et al. Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro. J. Pharmacol. Exp. Ther. 2018. Vol. 364. No. 1. P. 38–45. https://doi.org/10.1124/jpet.117.244095
  79. Neumann S., Eliseeva E., McCoy J.G. et al. A new small-molecule antagonist inhibits Graves' disease antibody activation of the TSH receptor. J. Clin. Endocrinol. Metab. 2011. Vol. 96. No. 2. P. 548–554. https://doi.org/10.1210/jc.2010-1935
  80. Neumann S., Huang W., Eliseeva E. et al. A small molecule inverse agonist for the human thyroid-stimulating hormone receptor. Endocrinology. 2010. Vol. 151. No. 7. P. 3454–3459. https://doi.org/10.1210/en.2010-0199
  81. Neumann S., Huang W., Titus S. et al. Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. Proc. Natl. Acad. Sci. U S A. 2009. Vol. 106. No. 30. P. 12471–12476. https://doi.org/10.1073/pnas.0904506106
  82. Neumann S., Kleinau G., Costanzi S. et al. A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology. 2008. Vol. 149. No. 12. P. 5945–5950. https://doi.org/10.1210/en.2008-0836
  83. Neumann S., Malik S.S., Marcus-Samuels B. et al. Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by Gs and Gi/o Proteins. Mol. Pharmacol. 2020. Vol. 97. No. 1. P. 2–8. https://doi.org/10.1124/mol.119.117382
  84. Neumann S., Nir E.A., Eliseeva E. et al. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology. 2014. Vol. 155. No. 1. P. 310–314. https://doi.org/10.1210/en.2013-1835
  85. Noh J.Y., Watanabe N., Ito K. et al. Safety, pharmacokinetics, and potential benefits of TSH-receptor-specific monoclonal autoantibody K1-70TM in Japanese Graves' disease patients: results of a phase 1 trial. Endocr. J. 2025. https://doi.org/10.1507/endocrj.EJ25-0043
  86. Núñez Miguel R., Sanders P., Allen L. et al. Structure of full-length TSH receptor in complex with antibody K1-70™. J. Mol. Endocrinol. 2022. Vol. 70. No. 1. e220120. https://doi.org/10.1530/JME-22-0120
  87. Núñez Miguel R., Sanders J., Chirgadze D.Y., Furmaniak J., Rees Smith B. Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein-protein interactions. J. Mol. Endocrinol. 2009. Vol. 42. No. 5. P. 381–395. https://doi.org/10.1677/JME-08-0152
  88. Ortiga-Carvalho T.M., Chiamolera M.I., Pazos-Moura C.C., Wondisford F.E. Hypothalamus-Pituitary-Thyroid Axis. Compr. Physiol. 2016. Vol. 6. No. 3. P. 1387–1428. https://doi.org/10.1002/cphy.c150027
  89. Parent E.E., Gleba J.J., Knight J.A. et al. Zirconium-89 Labeled Antibody K1-70 for PET Imaging of Thyroid-stimulating Hormone Receptor Expression in Thyroid Cancer. Mol. Imaging Biol. 2024. Vol. 26. No. 5. P. 847–857. https://doi.org/10.1007/s11307-024-01945-7
  90. Parra-Montes de Oca M.A., Sotelo-Rivera I., Gutiérrez-Mata A., Charli J.L., Joseph-Bravo P. Sex Dimorphic Responses of the Hypothalamus-Pituitary-Thyroid Axis to Energy Demands and Stress. Front. Endocrinol. (Lausanne). 2021. Vol. 12. 746924. https://doi.org/10.3389/fendo.2021.746924
  91. Postiglione M.P., Parlato R., Rodriguez-Mallon A. et al. Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland. Proc. Natl. Acad. Sci. U S A. 2002. Vol. 99. No. 24. P. 15462–15467. https://doi.org/10.1073/pnas.242328999
  92. Prummel M.F., Brokken L.J., Meduri G. et al. Expression of the thyroid-stimulating hormone receptor in the folliculo-stellate cells of the human anterior pituitary. J. Clin. Endocrinol. Metab. 2000. Vol. 85. No. 11. P. 4347–4353. https://doi.org/10.1210/jcem.85.11.6991
  93. Prummel M.F., Brokken L.J., Wiersinga W.M. Ultra short-loop feedback control of thyrotropin secretion. Thyroid. 2004. Vol. 14. No. 10. P. 825–829. https://doi.org/10.1089/thy.2004.14.825
  94. Querat B. Unconventional Actions of Glycoprotein Hormone Subunits: A Comprehensive Review. Front. Endocrinol. (Lausanne). 2021. Vol. 12. 731966. https://doi.org/10.3389/fendo.2021.731966
  95. Rapoport B., McLachlan S.M. The thyrotropin receptor in Graves' disease. Thyroid. 2007. Vol. 17. No. 10. P. 911–922. https://doi.org/10.1089/thy.2007.0170
  96. Ray A.P., Thakur N., Pour N.G., Eddy M.T. Dual mechanisms of cholesterol-GPCR interactions that depend on membrane phospholipid composition. Structure. 2023. Vol. 31. No. 7. P. 836–847.e6. https://doi.org/10.1016/j.str.2023.05.001
  97. Rossi L., Paternoster M., Cammarata M., Bakkar S., Miccoli P. Levothyroxine therapy in thyroidectomized patients: ongoing challenges and controversies. Front. Endocrinol. (Lausanne). 2025. Vol. 16. 1582734. https://doi.org/10.3389/fendo.2025.1582734
  98. Sanders P., Young S., Sanders J. et al. Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. J. Mol. Endocrinol. 2011. Vol. 46. No. 2. P. 81–99. https://doi.org/10.1530/JME-10-0127
  99. Sarkar R., Bolel P., Kapoor A. et al. An Orally Efficacious Thyrotropin Receptor Ligand Inhibits Growth and Metastatic Activity of Thyroid Cancers. J. Clin. Endocrinol. Metab. 2024. Vol. 109. No. 9. P. 2306–2316. https://doi.org/10.1210/clinem/dgae114
  100. Schaarschmidt J., Nagel M.B.M., Huth S. et al. Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation. J. Biol. Chem. 2016. Vol. 291. No. 27. P. 14095–14108. https://doi.org/10.1074/jbc.M115.709659
  101. Schulze A., Kleinau G., Neumann S. et al. The intramolecular agonist is obligate for activation of glycoprotein hormone receptors. FASEB J. 2020. Vol. 34. No. 8. P. 11243–11256. https://doi.org/10.1096/fj.202000100R
  102. Shpakov A.O. Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands. Int. J. Mol. Sci. 2023. Vol. 24. No. 7. 6187. https://doi.org/10.3390/ijms24076187
  103. Shpakov A.O. Hormonal and Allosteric Regulation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor. Front. Biosci. (Landmark Ed). 2024. Vol. 29. No. 9. P. 313. https://doi.org/10.31083/j.fbl2909313
  104. Smith B.R. Autoantibodies to the TSH Receptor-from discovery to understanding the mechanisms of action and to new therapeutics. Endocr. J. 2025. https://doi.org/10.1507/endocrj.EJ25-0127
  105. Stephenson A., Lau L., Eszlinger M., Paschke R. The Thyrotropin Receptor Mutation Database Update. Thyroid. 2020. Vol. 30. No. 6. P. 931–935. https://doi.org/10.1089/thy.2019.0807
  106. Szymańska K., Kałafut J., Przybyszewska A. et al. FSHR Trans-Activation and Oligomerization. Front. Endocrinol. (Lausanne). 2018. Vol. 9. P. 760. https://doi.org/10.3389/fendo.2018.00760
  107. Taylor P.N., Albrecht D., Scholz A. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 2018. Vol. 14. No. 5. P. 301–316. https://doi.org/10.1038/nrendo.2018.18
  108. Trubacova R., Drastichova Z., Novotny J. Biochemical and physiological insights into TRH receptor-mediated signaling. Front. Cell. Dev. Biol. 2022. Vol. 10. 981452. https://doi.org/10.3389/fcell.2022.981452
  109. Tuncel M. Thyroid Stimulating Hormone Receptor. Mol. Imaging Radionucl. Ther. 2017. Vol. 26. Suppl. 1. P. 87–91. https://doi.org/10.4274/2017.26.suppl.10
  110. Turcu A.F., Kumar S., Neumann S. et al. A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J. Clin. Endocrinol. Metab. 2013. Vol. 98. No. 5. P. 2153–2159. https://doi.org/10.1210/jc.2013-1149
  111. Urizar E., Montanelli L., Loy T. et al. Glycoprotein hormone receptors: link between receptor homodimerization and negative cooperativity. EMBO J. 2005. Vol. 24. No. 11. P. 1954–1964. https://doi.org/10.1038/sj.emboj.7600686
  112. Vassart G., Dumont J.E. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr. Rev. 1992. Vol. 13. No. 3. P. 596–611. https://doi.org/10.1210/edrv-13-3-596
  113. Vieira I.H., Rodrigues D., Paiva I. The Mysterious Universe of the TSH Receptor. Front. Endocrinol. (Lausanne). 2022. Vol. 13. 944715. https://doi.org/10.3389/fendo.2022.944715
  114. Von Gall C., Weaver D.R., Moek J. et al. Melatonin plays a crucial role in the regulation of rhythmic clock gene expression in the mouse pars tuberalis. Ann. N. Y. Acad. Sci. 2005. Vol. 1040. P. 508–511. https://doi.org/10.1196/annals.1327.105
  115. Wide L., Eriksson K. Thyrotropin N-glycosylation and Glycan Composition in Severe Primary Hypothyroidism. J. Endocr. Soc. 2021. Vol. 5. No. 4. bvab006. https://doi.org/10.1210/jendso/bvab006
  116. Wondisford F.E. The thyroid axis just got more complicated. J. Clin. Invest. 2002. Vol. 109. No. 11. P. 1401–1402. https://doi.org/10.1172/JCI15865
  117. Xiang P., Latif R., Morshed S., Davies T.F. Hypothyroidism Induced by a TSH Receptor Peptide-Implications for Thyroid Autoimmunity. Thyroid. 2024. Vol. 34. No. 12. P. 1513–1521. https://doi.org/10.1089/thy.2024.0089
  118. Xiang T., Zhang S., Li Q. et al. GPHB5 Is a Biomarker in Women With Metabolic Syndrome: Results From Cross-Sectional and Intervention Studies. Front. Endocrinol. (Lausanne). 2022. Vol. 13. 893142. https://doi.org/10.3389/fendo.2022.893142
  119. Xu S., Peng Y., Li X. et al. TSHR in thyroid cancer: bridging biological insights to targeted strategies. Eur. Thyroid J. 2025. Vol. 14. No. 4. e240369. https://doi.org/10.1530/ETJ-24-0369
  120. Yang Q., Li J., Kou C. et al. Presence of TSHR in NK Cells and Action of TSH on NK Cells. Neuroimmunomodulation. 2022. Vol. 29. No. 1. P. 77–84. https://doi.org/10.1159/000516925
  121. Yeste D., Baz-Redón N., Antolín M. et al. Genetic and Functional Studies of Patients with Thyroid Dyshormonogenesis and Defects in the TSH Receptor (TSHR). Int. J. Mol. Sci. 2024. Vol. 25. No. 18. 10032. https://doi.org/10.3390/ijms251810032
  122. Ząbczyńska M., Kozłowska K., Pocheć E. Glycosylation in the Thyroid Gland: Vital Aspects of Glycoprotein Function in Thyrocyte Physiology and Thyroid Disorders. Int. J. Mol. Sci. 2018. Vol. 19. No. 9. 2792. https://doi.org/10.3390/ijms19092792
  123. Zhang Y., Tan Y., Zhang Z. et al. Targeting Thyroid-Stimulating Hormone Receptor: A Perspective on Small-Molecule Modulators and Their Therapeutic Potential. J. Med. Chem. 2024. Vol. 67. No. 18. P. 16018–16034. https://doi.org/10.1021/acs.jmedchem.4c01525
  124. Zoenen M., Urizar E., Swillens S., Vassart G., Costagliola S. Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers. Nat. Commun. 2012. Vol. 3. 1007. https://doi.org/10.1038/ncomms1991

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 Russian Academy of Sciences

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).