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Ras homolog enriched in striatum inhibits the functional activity of wild type thyrotropin, follicle-stimulating hormone, luteinizing hormone receptors and activating thyrotropin receptor mutations by altering their expression in COS-7 cells

Journal of Endocrinological Investigation volume 30, pages 279–284 (2007)Cite this article

Abstract

Ras homolog enriched in striatum (Rhes) is a member of the Ras family of small GT-Pases detected in the thyroid. Rhes inhibits signal transduction from Gas protein. In this study we investigated whether Rhes can interfere with stimulation of cAMP/protein kinase A (PKA) pathway of TSH, FSH and LH receptors (TSHr, FSHr, LHr) and of activated TSHr mutants. Receptors were transiently transfected in COS-7 cells with or without Rhes; cAMP was evaluated in basal conditions and after hormone stimulation. Constitutive and bovine TSH (bTSH)-stimulated activity of wild type (wt) and mutated TSHr was inhibited after Rhes co-transfection. Rhes decreased cAMP after FSH and hCG β-subunit (βhCG) stimulation in cells expressing the cognate receptors. In binding experiments Rhes, as another membrane protein, sodium/iodide symporter (NIS), reduced membrane expression of wt TSHr (wtTSHr). In conclusion, Rhes can interfere with the functional activity of wt and mutated TSHr and with the respective hormone-stimulated cAMP production of FSHr and LHr. This interference is not specific and due to the co-expression of two membrane proteins.

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References

  1. Falk JD, Vargiu P, Foye PE, et al. Rhes: A striatal-specific Ras homolog related to Dexras1. J Neurosci Res 1999, 57: 782–8.

    CAS  PubMed  Article  Google Scholar 

  2. Vargiu P, Morte B, Manzano J, et al. Thyroid hormone regulation of Rhes, a novel Ras homolog gene expressed in the striatum. Brain Res Mol Brain Res 2001, 94: 1–8.

    CAS  PubMed  Article  Google Scholar 

  3. St Croix B, Rago C, Velculescu V, et al. Genes expressed in human tumor endothelium. Science 2000, 289: 1197–202.

    Article  Google Scholar 

  4. Spano D, Branchi I, Rosica A, et al. Rhes is involved in striatal function. Mol Cell Biol 2004, 24: 5788–96.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  5. Vargiu P, De Abajo R, Garcia-Ranea JA, et al. The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors. Oncogene 2004, 23: 559–68.

    CAS  PubMed  Article  Google Scholar 

  6. Cismowski MJ, Takesono A, Ma C, et al. Genetic screens in yeast to identify mammalian nonreceptor modulators of G-protein signaling. Nat Biotechnol 1999, 17: 878–83.

    CAS  PubMed  Article  Google Scholar 

  7. Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyreocyte function and growth. Endocr Rev 1992, 13: 596–611.

    CAS  PubMed  Google Scholar 

  8. Nagayama Y, Rapoport B. The thyrotropin receptor 25 years after its discovery: new insight after its molecular cloning. Mol Endocrinol 1992, 6: 145–56.

    CAS  PubMed  Google Scholar 

  9. Laurent E, Mockel J, Van Sande J, Graff I, Dumont JE. Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid. Mol Cell Endocrinol 1987, 52: 273–8.

    CAS  PubMed  Article  Google Scholar 

  10. Van Sande J, Raspe E, Perret J, et al. Thyrotropin activates both the cAMP and the PIP2 cascades in CHO cells expressing the human cDNA of TSH receptor. Mol Cell Endocrinol 1990, 74: R1–6.

    PubMed  Article  Google Scholar 

  11. Allgeier A, Offermans S, Van Sande J, Spicher K, Schultz G, Dumont JE. The human thyrotropin receptor activates G-protein Gs and Gq11. J Biol Chem 1994, 269: 13733–5.

    CAS  PubMed  Google Scholar 

  12. Van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J, Vassart G. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab 1995, 80: 2577–85.

    PubMed  Google Scholar 

  13. Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993, 365: 649–51.

    CAS  PubMed  Article  Google Scholar 

  14. Parma J, Van Sande J, Swillens S, Tonacchera M, Dumont JE, Vassart G. Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3′,5′-monophosphate and inositol phosphate-Ca2+ cascades. Mol Endocrinol 1995, 9: 725–33.

    CAS  PubMed  Google Scholar 

  15. Dupre L, Parma J, Van Sande J, et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 1994, 7: 396–401.

    Article  Google Scholar 

  16. Kopp P, Van Sande J, Parma J, et al. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin receptor gene. N Engl J Med 1995, 332: 150–4.

    CAS  PubMed  Article  Google Scholar 

  17. Tonacchera M, Chiovato L, Pinchera A, et al. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab 1998, 83: 492–8.

    CAS  PubMed  Google Scholar 

  18. Tonacchera M, Van Sande J, Cetani F, et al. Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia. J Clin Endocrinol Metab 1996, 81: 547–54.

    CAS  PubMed  Google Scholar 

  19. Lopata MA, Cleveland DW, Solner-Webb B. High level transient expression of a chloramphenicol acetyl transferase gene by DEAE-dextran mediated DNA transfection coupled with a dimethyl sulfoxide or glycerol shock treatment. Nucleic Acids Res 1984, 12: 5707–17.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  20. Cetani F, Tonacchera M, Vassart G. Differential effects of NaCl concentration on the constitutive activity of the thyrotropin and the luteinizing hormone/chorionic gonadotropin receptors. FEBS Letters 1996, 378: 27–31.

    CAS  PubMed  Article  Google Scholar 

  21. Jacobs C, Pirson I. Pitfalls in the use of transfected overexpression systems to study membrane proteins function: the case of TSH receptor and PRA1. Mol Cell Endocrinol 2003, 209: 71–5.

    CAS  PubMed  Article  Google Scholar 

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Affiliations

  1. Dipartimento di Endocrinologia, Università di Pisa, Via Paradisa 2, 56124, Pisa, Italy

    P. Agretti, G. De Marco, A. Pinchera, P. Vitti & M. Tonacchera MD

  2. Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, Madrid, Spain

    J. Bernal

Authors
  1. P. Agretti
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  2. G. De Marco
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  3. A. Pinchera
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  4. P. Vitti
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  5. J. Bernal
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  6. M. Tonacchera MD
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Correspondence to M. Tonacchera MD.

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Agretti, P., De Marco, G., Pinchera, A. et al. Ras homolog enriched in striatum inhibits the functional activity of wild type thyrotropin, follicle-stimulating hormone, luteinizing hormone receptors and activating thyrotropin receptor mutations by altering their expression in COS-7 cells. J Endocrinol Invest 30, 279–284 (2007). https://doi.org/10.1007/BF03346294

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  • DOI: https://doi.org/10.1007/BF03346294

Key-words

  • Rhes
  • G-protein coupled receptors
  • cAMP
  • PKA