Evolution of the thyrotropin receptor: a G protein coupled receptor with an intrinsic capacity to dimerize

Kaczur, V.; Puskás, László G.; Takács, Mária; Rácz, I; Szendroi, Andrea; Tóth, Sára; Nagy, Zsuzsanna; Szalai, Csaba; Balázs, Csaba; Falus, András; Knudsen, Bjarne; Farid, Nadir R.

doi:10.1016/s1096-7192(03)00036-2

Cited by 25 publications

(12 citation statements)

References 41 publications

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“…It therefore appears that the role of glycosylation in receptor guanylyl cyclases has evolved specifically for each protein, in a species-dependent manner. Species-specific novel glycosylation sites may impart an alternate means of regulating receptor activity as seen in the primate ␤2-adrenergic receptor (51), the tetrapod epidermal growth factor receptor (52), and the thyroid-stimulating hormone receptor (53).…”

Section: Discussionmentioning

confidence: 99%

Site-specific N-Linked Glycosylation of Receptor Guanylyl Cyclase C Regulates Ligand Binding, Ligand-mediated Activation and Interaction with Vesicular Integral Membrane Protein 36, VIP36

Arshad

Ballal

Visweswariah

2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Site-specific N-Linked Glycosylation of Receptor Guanylyl Cyclase C Regulates Ligand Binding, Ligand-mediated Activation and Interaction with Vesicular Integral Membrane Protein 36, VIP36

Arshad

Ballal

Visweswariah

2013

Journal of Biological Chemistry

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“…The introduction of the D633K mutation also strongly reduced TSHR activity (Table 1), most likely also by disturbing the intramolecular H-bond network and lowering the mobility of the 6th and 7th TMD. In addition, an influence of the 6th TMD on TSHR dimerization is discussed (46,47), which might be another explanation for the impaired G-protein activation caused by D633K. In our published TSHR model, however, D633 points into a space between the helices of the 6th, 7th and 3rd TMD, right in the center of the sevenhelix bundle (36).…”

Section: Discussionmentioning

confidence: 88%

Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation

Neumann

Claus²,

Paschke

2005

eur j endocrinol

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Objective: The molecular mechanisms of TSH receptor (TSHR) activation and intramolecular signal transduction are largely unknown. Deletion of the extracellular domain (ECD) of the TSHR results in increased constitutive activity, which suggests a self-inhibitory interaction between the ECD and the extracellular loops (ECLs) or the transmembrane domains (TMDs). To investigate these potential interactions and to pursue the idea that mutations in the ECD affect the constitutive activity of mutants in the ECLs or TMDs we generated double mutants between position 281 in the ECD and mutants in all three ECLs as well as the 6th TMD. Design: We combined mutation S281D, characterized by an impaired TSH-stimulated cAMP response, with the constitutively activating in vivo mutations I486F (1st ECL), I568T (2nd ECL), V656F (3rd ECL) and D633F (6th TMD). Further, we constructed double mutants containing the constitutively activating mutation S281N and one of the inactivating mutations D474E, T477I (1st ECL) and D633K (6th TMD). Results: The cAMP level of the double mutants with S281N and the inactive mutants in the 1st ECL was decreased below the level of the inactive single mutants, demonstrating that a constitutively activating mutation in the ECD cannot bypass disruption of signal transduction in the serpentine domain. In double mutants with S281D, basal and TSH-induced cAMP and inositol phosphate production of constitutively active mutants was reduced to the level of S281D. Conclusion: The dominance of S281D and the dependence of constitutively activating mutations in the ECLs on the functionally intact ECD strongly suggest that interactions between these receptor domains are required for TSHR activation and intramolecular signal transduction.European Journal of Endocrinology 152 625-634

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“…Upon the influence of oxidative stress and some cytokines (e.g. interferon) HLA Class II antigens are also expressed and this process is crucial in the presentation of autoantigens [1,14,17,18]. Our previous in vitro studies have shown that HLA Class II antigens are present only in 1 to 2% of a culture of human thyroid cells; however this value increases up to 30 to 40% under the influence of interferon gamma or oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular polymorphism of TG and effects exerted on the immunogenicity of the molecule by external factors (e.g. iodine) may play a role in the fact that anti-TG antibodies decrease in the presence of selenium to a lesser extent as compared to anti-TPO antibodies [13,14,18,[23][24][25]. As for the TPO decreasing effect of Se, the literature is not coherent.…”

Section: Discussionmentioning

confidence: 99%

The effect of selenium therapy on autoimmune thyroiditis

Balázs¹,

Fehér²

2009

Clinical and Experimental Medical Journal

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AbbreviationsAT = autoimmune thyroiditis; n. s. = not significant; Se = selenium; T2 = di-iodothyronine; T3 = tri-iodothyronine; T4 = thyroxine; fT3 = free tri-iodothyronine; fT4 = free thyroxine; TAS = total antioxidant status; TG = thyroglobulin; TSH = thyroid-stimulating hormone; TPO = thyroid peroxidase enzyme; vs. = versus Due to its antioxidant capacity, the essential trace element selenium exerts complex effects on the endocrine and immune systems. Selenium may have an important role in autoimmune thyroid diseases because levels of free oxygen radicals are elevated during physiological thyroid hormone synthesis. Objective: To determine whether selenium therapy can influence anti-thyroid peroxidase and anti-thyroglobulin antibody levels or if there is a correlation between antioxidant capacity and autoantibody titres. Method: 132 patients with autoimmune thyroiditis were investigated in a prospective, blinded and placebo controlled study. L-thyroxine substitution therapy was administered in both groups and TSH levels remained in the normal range. The selenium treated group (70 patients, 68 female, mean age 41.4 ! 9.5 years) was compared with the placebo treated group (62 patients, 61 female, mean age 42.7 ! 8.3 years). Selenium therapy included oral administration of 100 µg L-seleno-methionine tablets twice a day for a year. Determinations of TSH, fT4 and fT3 as well as antibody levels were carried out by chemoluminescent method. Total antioxidant capacity was determined by Randox kit, and serum selenium levels were measured by atomic absorption technique. In the course of the study patients were controlled every third month and at the end of the one year long observation period. Results: Selenium levels in untreated patients were significantly lower than those in treated patients and controls. The fT3/fT4 ratio proved to be higher in patients after selenium therapy. Titres of antithyroid antibodies (mostly antithyroid peroxidase) significantly decreased at the end of the study. An inverse correlation was found between antioxidant capacity and antithyroid peroxidase levels. The volume of thyroid gland slightly diminished in treated patients. No adverse reactions were observed. Conclusion: Selenium completed with L-thyroxine is a suitable therapy of patients with autoimmune thyroiditis.

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Evolution of the thyrotropin receptor: a G protein coupled receptor with an intrinsic capacity to dimerize

Cited by 25 publications

References 41 publications

Site-specific N-Linked Glycosylation of Receptor Guanylyl Cyclase C Regulates Ligand Binding, Ligand-mediated Activation and Interaction with Vesicular Integral Membrane Protein 36, VIP36

Site-specific N-Linked Glycosylation of Receptor Guanylyl Cyclase C Regulates Ligand Binding, Ligand-mediated Activation and Interaction with Vesicular Integral Membrane Protein 36, VIP36

Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation

The effect of selenium therapy on autoimmune thyroiditis

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