title: Constitutive activation of the thyroid-stimulating hormone receptor (TSHR) by mutating Ile691 in the cytoplasmic tail segment.
abstract: BACKGROUND
  Autosomal dominant non-autoimmune hyperthyroidism (ADNAH) is a rare genetic disorder of the endocrine system. Molecular genetic studies in ADNAH have revealed heterozygous germline mutations in the TSHR. To data, mutations leading to an increase in the constitutive activation of the TSHR have been described in the transmembrane segments, exoloops and cytoplasmic loop of TSHR. These mutations result in constitutive activation of the G(αs)/cAMP or G(αq/11)/inositol phosphate (IP) pathways, which stimulate thyroid hormone production and thyroid proliferation.
  
  
  RESULTS
  In a previous study, we reported a new TSHR mutation located in the C-terminal domain of TSHR, which results in a substitution of the conserved Ile(691) for Phe. In this study, to address the question of whether the I691F mutated receptor could be responsible for G(αs)/cAMP or G(αq/11)/IP constitutive activity, wild-type and TSHR mutants were expressed in COS-7 cells to determine cAMP constitutive activity and IP formation. Compared to the cell surface with expression of the A623V mutated receptor as positive control, the I691F mutated receptor showed a slight increase of cAMP accumulation. Furthermore, I691F resulted in constitutive activation of the G(αq/11)/IP signaling pathway.
  
  
  CONCLUSIONS
  Our results indicate that Ile(691) not only contributes to keeping TSHR inactive in the G(αs)/cAMP pathways but also in the G(αq/11)/IP cascade.
authors.affiliation: Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tian Jin, China. liu.zheng1111@gmail.com
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Feiyue
authors.initials: F
authors.lastname: Fan
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Xiao
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000242:Cyclic AMP / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics; D007295:Inositol Phosphates / Q000378:metabolism; D007532:Isoleucine / Q000235:genetics; D009154:Mutation; D011487:Protein Conformation; D035583:Rare Diseases; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D007295:Inositol Phosphates; D011989:Receptors, Thyrotropin; D007532:Isoleucine; D000242:Cyclic AMP; D043802:GTP-Binding Protein alpha Subunits, Gq-G11