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1
Unfried, Claudia, Nariman Ansari, Shinobu Yasuo, Horst-Werner Korf, and Charlotte von Gall. "Impact of Melatonin and Molecular Clockwork Components on the Expression of Thyrotropin β-Chain (Tshb) and the Tsh Receptor in the Mouse Pars Tuberalis." Endocrinology 150, no. 10 (July 9, 2009): 4653–62. http://dx.doi.org/10.1210/en.2009-0609.
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Abstract Photoperiodic regulation of reproduction in birds and mammals involves thyrotropin β-chain (TSHb), which is secreted from the pars tuberalis (PT) and controls the expression of deiodinase type 2 and 3 in the ependymal cell layer of the infundibular recess (EC) via TSH receptors (TSHRs). To analyze the impact of melatonin and the molecular clockwork on the expression of Tshb and Tshr, we investigated melatonin-proficient C3H wild-type (WT), melatonin receptor 1-deficient (MT1-/-) or clockprotein PERIOD1-deficient (mPER1-/-) mice. Expression of Tshb and TSHb immunoreactivity in PT were low during day and high during the night in WT, high during the day and low during the night in mPER1-deficient, and equally high during the day and night in MT1-deficient mice. Melatonin injections into WT acutely suppressed Tshb expression. Transcription assays showed that the 5′ upstream region of the Tshb gene could be controlled by clockproteins. Tshr levels in PT were low during the day and high during the night in WT and mPER1-deficient mice and equally low in MT1-deficient mice. Tshr expression in the EC did not show a day/night variation. Melatonin injections into WT acutely induced Tshr expression in PT but not in EC. TSH stimulation of hypothalamic slice cultures of WT induced phosphorylated cAMP response element-binding protein in PT and EC and deiodinase type 2 in the EC. Our data suggest that Tshb expression in PT is controlled by melatonin and the molecular clockwork and that melatonin activates Tshr expression in PT but not in EC. They also confirm the functional importance of TSHR in the PT and EC.
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Tagami, Tetsuya, Kaho Hiroshima-Hamanaka, Hironobu Umakoshi, Mika Tsuiki-Naruse, Toru Kusakabe, Noriko Satoh-Asahara, Akira Shimatsu, and Kenji Moriyama. "Experimental Reproduction of Dynamic Fluctuation of TSH Receptor–Binding Antibodies Between Stimulation and Inhibition." Journal of the Endocrine Society 3, no. 12 (September 23, 2019): 2361–73. http://dx.doi.org/10.1210/js.2019-00012.
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Abstract Context Hyperthyroidism in Graves disease (GD) is caused by autoantibody stimulation of the TSH receptor (TSHR). TSHR autoantibody (TSHR-Ab) activity is measured routinely by inhibition of labeled ligand (TSH or M22) binding to the TSHR [TSH-binding inhibitory immunoglobulins (TBIIs)] or by stimulation of cAMP production in isolated cells [TSH receptor–stimulating antibodies (TSAbs)]. Usually, measurements of TSHR-Abs by TBIIs agree reasonably well with TSAb values at least in the setting of hyperthyroidism, and both measurements tend to change in parallel during treatment with some exceptions. In this study, we describe three unusual cases, which illustrate nearly pure stimulating, blocking, or neutral properties of TSHR-Abs. Objective Whether patient serum TSHR-Abs can be reproduced by mixtures of human monoclonal autoantibodies to the TSHR was studied because the sera in most patients show moderate properties having both of TBII and TSAb activities. Design We compared the TBII and TSAb activities of serum from four unusual patients in detail with mixtures of human monoclonal TSHR-Abs (mAbs) M22 (stimulating), K1-18 (stimulating), and K1-70 (blocking). Results Characteristic of a patient’s serum was similar to M22 or K1-18, another was similar to K1-70, whereas another was similar to a mixture of K1-70 and M22 (or K1-18). Additionally, some patients seemed to have neutral TSHR-Abs in their sera. Conclusions Our studies suggest that the characteristics of TSHR-Abs in the patient serum can be mimicked by mixtures of human mAbs to the TSHR, stimulating, blocking, and neutral if any.
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Neumann, Susanne, Elena Eliseeva, Joshua G. McCoy, Giorgio Napolitano, Cesidio Giuliani, Fabrizio Monaco, Wenwei Huang, and Marvin C. Gershengorn. "A New Small-Molecule Antagonist Inhibits Graves' Disease Antibody Activation of the TSH Receptor." Journal of Clinical Endocrinology & Metabolism 96, no. 2 (February 1, 2011): 548–54. http://dx.doi.org/10.1210/jc.2010-1935.
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abstract Context: Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate the TSH receptor (TSHR). We previously reported the first small-molecule antagonist of human TSHR and showed that it inhibited receptor signaling stimulated by sera from four patients with GD. Objective: Our objective was to develop a better TSHR antagonist and use it to determine whether inhibition of TSAb activation of TSHR is a general phenomenon. Design: We aimed to chemically modify a previously reported small-molecule TSHR ligand to develop a better antagonist and determine whether it inhibits TSHR signaling by 30 GD sera. TSHR signaling was measured in two in vitro systems: model HEK-EM293 cells stably overexpressing human TSHRs and primary cultures of human thyrocytes. TSHR signaling was measured as cAMP production and by effects on thyroid peroxidase mRNA. Results: We tested analogs of a previously reported small-molecule TSHR inverse agonist and selected the best NCGC00229600 for further study. In the model system, NCGC00229600 inhibited basal and TSH-stimulated cAMP production. NCGC00229600 inhibition of TSH signaling was competitive even though it did not compete for TSH binding; that is, NCGC00229600 is an allosteric inverse agonist. NCGC00229600 inhibited cAMP production by 39 ± 2.6% by all 30 GD sera tested. In primary cultures of human thyrocytes, NCGC00229600 inhibited TSHR-mediated basal and GD sera up-regulation of thyroperoxidase mRNA levels by 65 ± 2.0%. Conclusion: NCGC00229600, a small-molecule allosteric inverse agonist of TSHR, is a general antagonist of TSH receptor activation by TSAbs in GD patient sera.
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Krieger, Christine C., Susanne Neumann, and Marvin C. Gershengorn. "Is There Evidence for IGF1R-Stimulating Abs in Graves’ Orbitopathy Pathogenesis?" International Journal of Molecular Sciences 21, no. 18 (September 8, 2020): 6561. http://dx.doi.org/10.3390/ijms21186561.
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In this review, we summarize the evidence against direct stimulation of insulin-like growth factor 1 receptors (IGF1Rs) by autoantibodies in Graves’ orbitopathy (GO) pathogenesis. We describe a model of thyroid-stimulating hormone (TSH) receptor (TSHR)/IGF1R crosstalk and present evidence that observations indicating IGF1R’s role in GO could be explained by this mechanism. We evaluate the evidence for and against IGF1R as a direct target of stimulating IGF1R antibodies (IGF1RAbs) and conclude that GO pathogenesis does not involve directly stimulating IGF1RAbs. We further conclude that the preponderance of evidence supports TSHR as the direct and only target of stimulating autoantibodies in GO and maintain that the TSHR should remain a major target for further development of a medical therapy for GO in concert with drugs that target TSHR/IGF1R crosstalk.
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Neumann, Susanne, Christine C. Krieger, and Marvin C. Gershengorn. "Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease." European Thyroid Journal 9, Suppl. 1 (2020): 59–65. http://dx.doi.org/10.1159/000511538.
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Graves’ disease (GD) is an autoimmune disease caused in part by thyroid-stimulating antibodies (TSAbs) that activate the thyroid-stimulating hormone receptor (TSHR). In Graves’ hyperthyroidism (GH), TSAbs cause persistent stimulation of thyroid cells leading to continuous thyroid hormone synthesis and secretion. Thyroid eye disease (TED), also called Graves’ orbitopathy, is an orbital manifestation of GD. We review the important roles of the TSHR and the insulin-like growth factor 1 receptor (IGF-1R) in the pathogenesis of TED and discuss a model of TSHR/IGF-1R crosstalk that considers two pathways initiated by TSAb activation of TSHR in the eye, an IGF-1R-independent and an IGF-1R-dependent signaling pathway leading to hyaluronan (HA) secretion in orbital fibroblasts. We discuss current and future therapeutic approaches targeting the IGF-1R and TSHR. Teprotumumab, a human monoclonal anti-IGF-1R-blocking antibody, has been approved as an effective treatment in patients with TED. However, as the TSHR seems to be the primary target for TSAbs in patients with GD, future therapeutic interventions directly targeting the TSHR, e.g. blocking antibodies and small molecule antagonists, are being developed and have the advantage to inhibit the IGF-1R-independent as well as the IGF-1R-dependent component of TSAb-induced HA secretion. Antigen-specific immunotherapies using TSHR peptides to reduce serum TSHR antibodies are being developed also. These TSHR-targeted strategies also have the potential to treat both GH and TED with the same drug. We propose that combination therapy targeting TSHR and IGF-1R may be an effective and better tolerated treatment strategy for TED.
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Neumann, Susanne, Eshel A. Nir, Elena Eliseeva, Wenwei Huang, Juan Marugan, Jingbo Xiao, Andrés E. Dulcey, and Marvin C. Gershengorn. "A Selective TSH Receptor Antagonist Inhibits Stimulation of Thyroid Function in Female Mice." Endocrinology 155, no. 1 (January 1, 2014): 310–14. http://dx.doi.org/10.1210/en.2013-1835.
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Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 μM for TSHR and greater than 30 μM for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease.
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Sanders, Jane, Yasuo Oda, Sara Roberts, Angela Kiddie, Tonya Richards, Jane Bolton, Vivienne McGrath, et al. "The Interaction of TSH Receptor Autoantibodies with 125I-Labelled TSH Receptor." Journal of Clinical Endocrinology & Metabolism 84, no. 10 (October 1, 1999): 3797–802. http://dx.doi.org/10.1210/jcem.84.10.6071.
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Abstract Detergent-solubilized porcine TSH receptor (TSHR) has been labeled with 125I using a monoclonal antibody to the C-terminal domain of the receptor. The ability of sera containing TSHR autoantibody to immunoprecipitate the labeled receptor was then investigated. Sera negative for TSHR autoantibody (as judged by assays based on inhibition of labeled TSH binding to detergent-solubilized porcine TSHR) immunoprecipitated about 4% of the labeled receptor, whereas sera with high levels of receptor autoantibody immunoprecipitated more than 25% of the labeled receptor. The ability to immunoprecipitate labeled TSHR correlated well with ability of the sera to inhibit labeled TSH binding to the receptor (r = 0.92; n = 63), and this is consistent with TSHR autoantibodies in these samples being directed principally to a region of the receptor closely related to the TSH binding site. Preincubation of labeled TSHR with unlabeled TSH before reaction with test sera inhibited the immunoprecipitation reaction, providing further evidence for a close relationship between the TSHR autoantibody binding site(s) and the TSH binding site. This was the case whether the sera had TSH agonist (i.e., thyroid stimulating) or TSH antagonist (i.e., blocking) activities, thus, providing no clear evidence for different regions of the TSHR being involved in forming the binding site(s) for TSHR autoantibodies with stimulating and with blocking activities. The ability of TSHR autoantibodies to stimulate cyclic AMP production in isolated porcine thyroid cells was compared with their ability to immunoprecipitate labeled porcine TSHR. A significant correlation was observed (r = 0.58; n = 50; P < 0.001) and the correlation was improved when stimulation of cyclic AMP production was compared with inhibition of labeled TSH binding to porcine TSHR (r = 0.76). Overall, our results indicate that TSHR autoantibodies bind principally to a region on the TSHR closely related to the TSH binding site, and this seems to be the case whether the autoantibodies act as TSH agonists or antagonists.
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Bäck, Christer M., Stefanie Stohr, Eva A. M. Schäfer, Heike Biebermann, Ingrid Boekhoff, Andreas Breit, Thomas Gudermann, and Thomas R. H. Büch. "TSH induces metallothionein 1 in thyrocytes via Gq/11- and PKC-dependent signaling." Journal of Molecular Endocrinology 51, no. 1 (April 23, 2013): 79–90. http://dx.doi.org/10.1530/jme-12-0200.
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Metallothioneins (MTs) are cytoprotective proteins acting as scavengers of toxic metal ions or reactive oxygen species. MTs are upregulated in follicular thyroid carcinoma and are regarded as a marker of thyroid stress in Graves' disease. However, the mechanism of MT regulation in thyrocytes is still elusive. In other cellular systems, cAMP-, calcium-, or protein kinase C (PKC)-dependent signaling cascades have been shown to induce MT expression. Of note, all of these three pathways are activated following the stimulation of the TSH receptor (TSHR). Thus, we hypothesized that TSH represents a key regulator of MT expression in thyrocytes. In fact, TSHR stimulation induced expression of MT isoform 1X (MT1X) in human follicular carcinoma cells. In these cells, Induction of MT1X expression critically relied on intact Gq/11signaling of the TSHR and was blocked by chelation of intracellular calcium and inhibition of PKC. TSHR-independent stimulation of cAMP formation by treating cells with forskolin also led to an upregulation of MT1X, which was completely dependent on PKA. However, inhibition of PKA did not affect the regulation of MT1X by TSH. As in follicular thyroid carcinoma cells, TSH also induced MT1 protein in primary human thyrocytes, which was PKC dependent as well. In summary, these findings indicate that TSH stimulation induces MT1X expression via Gq/11and PKC, whereas cAMP–PKA signaling does not play a predominant role. To date, little has been known regarding cAMP-independent effects of TSHR signaling. Our findings extend the knowledge about the PKC-mediated functions of the TSHR.
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Krieger, Christine C., Robert F. Place, Carmine Bevilacqua, Bernice Marcus-Samuels, Brent S. Abel, Monica C. Skarulis, George J. Kahaly, Susanne Neumann, and Marvin C. Gershengorn. "TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis." Journal of Clinical Endocrinology & Metabolism 101, no. 6 (June 1, 2016): 2340–47. http://dx.doi.org/10.1210/jc.2016-1315.
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Abstract Context: The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role. Objective: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. Design/Setting/Participants: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. Main Outcome Measures: Hyaluronan (hyaluronic acid [HA]) secretion was measured as a major biological response for GOF stimulation. IGF-1R autophosphorylation was used as a measure of direct IGF-1R activation. TSHR activation was determined through cAMP production. Results: A total of 42 out of 57 GO-Ig samples stimulated HA secretion. None of the GO-Ig samples exhibited evidence for IGF-1R autophosphorylation. Both anti-IGF-1R antibodies completely inhibited IGF-1 stimulation of HA secretion. By contrast, only 1 IGF-1R antibody partially blocked HA secretion stimulated by M22 or GO-Igs in a manner similar to linsitinib, whereas the other IGF-1R antibody had no effect on M22 or GO-Ig stimulation. These findings show that the IGF-1R is involved in GO-Igs stimulation of HA secretion without direct activation of IGF-1R. Conclusions: IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO.
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McLachlan, Sandra M., Holly Aliesky, Bianca Banuelos, Jessica Magana, Robert W. Williams, and Basil Rapoport. "Immunoglobulin Heavy Chain Variable Region and Major Histocompatibility Region Genes Are Linked to Induced Graves' Disease in Females From Two Very Large Families of Recombinant Inbred Mice." Endocrinology 155, no. 10 (October 1, 2014): 4094–103. http://dx.doi.org/10.1210/en.2014-1388.
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Abstract Graves' hyperthyroidism is caused by antibodies to the TSH receptor (TSHR) that mimic thyroid stimulation by TSH. Stimulating TSHR antibodies and hyperthyroidism can be induced by immunizing mice with adenovirus expressing the human TSHR A-subunit. Prior analysis of induced Graves' disease in small families of recombinant inbred (RI) female mice demonstrated strong genetic control but did not resolve trait loci for TSHR antibodies or elevated serum T4. We investigated the genetic basis for induced Graves' disease in female mice of two large RI families and combined data with earlier findings to provide phenotypes for 178 genotypes. TSHR antibodies measured by inhibition of TSH binding to its receptor were highly significantly linked in the BXD set to the major histocompatibility region (chromosome 17), consistent with observations in 3 other RI families. In the LXS family, we detected linkage between T4 levels after TSHR-adenovirus immunization and the Ig heavy chain variable region (Igvh, chromosome 12). This observation is a key finding because components of the antigen binding region of Igs determine antibody specificity and have been previously linked to induced thyroid-stimulating antibodies. Data from the LXS family provide the first evidence in mice of a direct link between induced hyperthyroidism and Igvh genes. A role for major histocompatibility genes has now been established for genetic susceptibility to Graves' disease in both humans and mice. Future studies using arrays incorporating variation in the complex human Ig gene locus will be necessary to determine whether Igvh genes are also linked to Graves' disease in humans.
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Misharin, Alexander V., Yuji Nagayama, Holly A. Aliesky, Yumiko Mizutori, Basil Rapoport, and Sandra M. McLachlan. "Attenuation of Induced Hyperthyroidism in Mice by Pretreatment with Thyrotropin Receptor Protein: Deviation of Thyroid-Stimulating to Nonfunctional Antibodies." Endocrinology 150, no. 8 (April 23, 2009): 3944–52. http://dx.doi.org/10.1210/en.2009-0181.
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Graves’-like hyperthyroidism is induced by immunizing BALB/c mice with adenovirus expressing the thyrotropin receptor (TSHR) or its A-subunit. Nonantigen-specific immune strategies can block disease development and some reduce established hyperthyroidism, but these approaches may have unforeseen side effects. Without immune stimulation, antigens targeted to the mannose receptor induce tolerance. TSHR A-subunit protein generated in eukaryotic cells binds to the mannose receptor. We tested the hypothesis that eukaryotic A-subunit injected into BALB/c mice without immune stimulation would generate tolerance and protect against hyperthyroidism induced by subsequent immunization with A-subunit adenovirus. Indeed, one sc injection of eukaryotic, glycosylated A-subunit protein 1 wk before im A-subunit-adenovirus immunization reduced serum T4 levels and the proportion of thyrotoxic mice decreased from 77 to 22%. Prokaryotic A-subunit and other thyroid proteins (thyroglobulin and thyroid peroxidase) were ineffective. A-subunit pretreatment reduced thyroid-stimulating and TSH-binding inhibiting antibodies, but, surprisingly, TSHR-ELISA antibodies were increased. Rather than inducing tolerance, A-subunit pretreatment likely expanded B cells that secrete nonfunctional antibodies. Follow-up studies supported this possibility and also showed that eukaryotic A-subunit administration could not reverse hyperthyroidism in mice with established disease. In conclusion, glycosylated TSHR A-subunit is a valuable immune modulator when used before immunization. It acts by deviating responses away from pathogenic toward nonfunctional antibodies, thereby attenuating induction of hyperthyroidism. However, this protein treatment does not reverse established hyperthyroidism. Our findings suggest that prophylactic TSHR A-subunit protein administration in genetically susceptible individuals may deviate the autoantibody response away from pathogenic epitopes and provide protection against future development of Graves’ disease.
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Agretti, Patrizia, Giuseppina De Marco, Melissa De Servi, Claudio Marcocci, Paolo Vitti, Aldo Pinchera, and Massimo Tonacchera. "Evidence for protein and mRNA TSHr expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation." European Journal of Endocrinology 152, no. 5 (May 2005): 777–84. http://dx.doi.org/10.1530/eje.1.01900.
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Objective: Thyroid-associated ophthalmopathy (TAO) is a chronic autoimmune disorder characterized by an increased volume of adipose/connective tissue in the human orbit. Design: The aim of this study was to investigate the thyrotropin receptor (TSHr) expression in orbital fibroblasts from TAO patients undergoing adipocytic differentiation. Methods: Retro-ocular tissue and skin were obtained from five patients undergoing orbital decompression surgery for TAO and placed in culture. Proliferating fibroblasts were subjected to adipocytic differentiation for 10 days. Total RNA was isolated from fibroblasts and was reverse transcribed. TSHr mRNA levels were determined by real-time PCR. cAMP was determined by radioimmunoassay (RIA) after fibroblast incubation with the substances to test. Results: Orbital differentiated fibroblasts became rounded and acquired lipid droplets. The amount of TSHr mRNA in these fibroblasts was higher than fibroblasts not subjected to adipocytic differentiation. Immunocytochemical analysis showed TSHr protein in differentiated orbital fibroblasts. Differentiated orbital fibroblasts stimulated with bovine (b) TSH showed a cAMP production greater than that in paired undifferentiated cultures. A specific thyroid-inhibiting antibody (TBAb) inhibited cAMP production after bTSH challenge, and a thyroid-stimulating antibody (TSAb) stimulated cAMP production in differentiated fibroblasts. Conclusions: We suggest that orbital fibroblasts subjected to adipocytic differentiation increase TSHr expression that responds specifically to bTSH and TSAb stimulation, and to TBAb inhibition.
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Valyasevi, Rosanee W., Dana Z. Erickson, Debra A. Harteneck, Charyl M. Dutton, Armin E. Heufelder, Soma C. Jyonouchi, and Rebecca S. Bahn. "Differentiation of Human Orbital Preadipocyte Fibroblasts Induces Expression of Functional Thyrotropin Receptor1." Journal of Clinical Endocrinology & Metabolism 84, no. 7 (July 1, 1999): 2557–62. http://dx.doi.org/10.1210/jcem.84.7.5838.
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Although the autoantigen involved in Graves’ hyperthyroidism is known to be the TSH receptor (TSHr), whether this antigen plays a primary role in the pathogenesis of Graves’ ophthalmopathy (GO) is unclear. We sought to determine whether fibroblasts derived from orbital adipose/connective tissue are capable of differentiating into adipocytes that bear immunoreactive and functional TSHr. In addition, we assessed relative levels of TSHr gene expression in normal and GO orbital adipose/connective tissue specimens. GO and normal orbital preadipocyte fibroblasts, cultured under conditions known to stimulate adipocyte differentiation, showed evidence of adipogenesis and positive immunostaining for TSHr protein. In addition, significantly more cAMP was produced in response to TSH stimulation in the differentiated cultures than in undifferentiated cultures derived from the same individuals’ cells. Other studies demonstrated relatively greater TSHr gene expression in GO than in normal orbital tissue specimens. These results indicate that orbital preadipocyte fibroblasts increase their TSHr expression with differentiation and suggest that these cells play an important role in the pathogenesis of GO. Furthermore, our studies support the concept that TSHr may be an important target antigen in this condition. Factors that stimulate adipocyte differentiation and TSHr expression in the orbit in GO have yet to be defined.
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Miller-Gallacher, Jennifer, Paul Sanders, Stuart Young, Andrew Sullivan, Stuart Baker, Samuel C. Reddington, Matthew Clue, et al. "Crystal structure of a ligand-free stable TSH receptor leucine-rich repeat domain." Journal of Molecular Endocrinology 62, no. 3 (April 2019): 117–28. http://dx.doi.org/10.1530/jme-18-0213.
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The crystal structures of the thyroid-stimulating hormone receptor (TSHR) leucine-rich repeat domain (amino acids 22–260; TSHR260) in complex with a stimulating human monoclonal autoantibody (M22TM) and in complex with a blocking human autoantibody (K1-70™) have been solved. However, attempts to purify and crystallise free TSHR260, that is not bound to an autoantibody, have been unsuccessful due to the poor stability of free TSHR260. We now describe a TSHR260 mutant that has been stabilised by the introduction of six mutations (H63C, R112P, D143P, D151E, V169R and I253R) to form TSHR260-JMG55TM, which is approximately 900 times more thermostable than wild-type TSHR260. These six mutations did not affect the binding of human TSHR monoclonal autoantibodies or patient serum TSHR autoantibodies to the TSHR260. Furthermore, the response of full-length TSHR to stimulation by TSH or human TSHR monoclonal autoantibodies was not affected by the six mutations. Thermostable TSHR260-JMG55TM has been purified and crystallised without ligand and the structure solved at 2.83 Å resolution. This is the first reported structure of a glycoprotein hormone receptor crystallised without ligand. The unbound TSHR260-JMG55TM structure and the M22 and K1-70 bound TSHR260 structures are remarkably similar except for small changes in side chain conformations. This suggests that neither the mutations nor the binding of M22TM or K1-70TM change the rigid leucine-rich repeat domain structure of TSHR260. The solved TSHR260-JMG55TM structure provides a rationale as to why the six mutations have a thermostabilising effect and provides helpful guidelines for thermostabilisation strategies of other soluble protein domains.
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Grommen, Sylvia V. H., Shusuke Taniuchi, Tom Janssen, Liliane Schoofs, Sumio Takahashi, Sakae Takeuchi, Veerle M. Darras, and Bert De Groef. "Molecular Cloning, Tissue Distribution, and Ontogenic Thyroidal Expression of the Chicken Thyrotropin Receptor." Endocrinology 147, no. 8 (August 1, 2006): 3943–51. http://dx.doi.org/10.1210/en.2005-1223.
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TSH and the interaction with its receptor (TSHR) in the thyroid gland play a crucial role in the pituitary-thyroid axis of all vertebrates. Released upon stimulation by TSH, thyroid hormones influence numerous processes in the body and are extremely important during the last week of chicken embryonic development. In this study, we have cloned and functionally characterized the chicken TSHR (cTSHR), which was found to be a G protein-coupled receptor consisting of 10 exons. Besides the full-length cDNA, we detected two splice variants lacking either exon 3, or exons 2 and 3, both part of the extracellular domain of the receptor. Bovine TSH increased intracellular cAMP levels in HEK-239 cells transiently expressing the full-length cTSHR (EC50 = 1.43 nm). In situ hybridization showed the expression of cTSHR mRNA in the thyroidal follicular cells. cTSHR mRNA expression, as determined by real-time PCR, was also found in several other tissues such as brain, pituitary, pineal gland, and retina, suggesting that the TSH-TSHR interaction is not only important in regulating thyroid function. TSHR mRNA expression in the thyroid gland did not change significantly during the last week of embryonic development, which suggests that an increased thyroidal sensitivity is not part of the cause of the concomitant increasing T4 levels.
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Mizutori, Yumiko, Chun-Rong Chen, Sandra M. McLachlan, and Basil Rapoport. "The Thyrotropin Receptor Hinge Region Is Not Simply a Scaffold for the Leucine-Rich Domain but Contributes to Ligand Binding and Signal Transduction." Molecular Endocrinology 22, no. 5 (May 1, 2008): 1171–82. http://dx.doi.org/10.1210/me.2007-0407.
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Abstract The glycoprotein hormone receptor hinge region connects the leucine-rich and transmembrane domains. The prevalent concept is that the hinge does not play a significant role in ligand binding and signal transduction. Portions of the hinge are redundant and can be deleted by mutagenesis or are absent in certain species. A minimal hinge will be more amenable to future investigation of its structure and function. We, therefore, combined and progressively extended previous deletions (Δ) in the TSH receptor (TSHR) hinge region (residues 277–418). TSHRΔ287–366, Δ287–371, Δ287–376, and Δ287–384 progressively lost their response to TSH stimulation of cAMP generation in intact cells, consistent with a progressive loss of TSH binding. The longest deletion (TSHRΔ287–384), reducing the hinge region from 141 to 43 amino acids, totally lost both functions. Surprisingly, however, with deletions extending from residues 371–384, constitutive (ligand-independent) activity increased severalfold, reversing the suppressive (inverse agonist) effect of the TSHR extracellular domain. TSHR-activating point mutations I486F and I568T in the first and second extracellular loops (especially the former) had reduced activity on a background of TSHRΔ287–371. In summary, our data support the concept that the TSHR hinge contributes significantly to ligand binding affinity and signal transduction. Residues within the hinge, particularly between positions 371–384, appear involved in ectodomain inverse agonist activity. In addition, the hinge is necessary for functionality of activating mutations in the first and second extracellular loops. Rather than being an inert linker between the leucine-rich and transmembrane domains, the TSHR hinge is a signaling-specificity domain.
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Ma, Risheng, Rauf Latif, and Terry F. Davies. "Thyrotropin-Independent Induction of Thyroid Endoderm from Embryonic Stem Cells by Activin A." Endocrinology 150, no. 4 (December 12, 2008): 1970–75. http://dx.doi.org/10.1210/en.2008-1374.
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To model the differentiation of thyroid epithelial cells, we examined embryoid bodies derived from undifferentiated murine embryonic stem cells treated with activin A to induce endoderm differentiation, the germ layer from which thyroid cells occur. The resulting endodermal cells were then further exposed to TSH and/or IGF-I for up to 21 d. Oct-4 and REX1 expression, required to sustain stem cell self-renewal and pluripotency, were appropriately down-regulated, whereas GATA-4, and α-fetoprotein, both endodermal-specific markers, increased as the embryonic stem cells were exposed to activin A. By d 5 culture, TSH receptor (TSHR) and sodium iodide symporter (NIS) gene and protein expression were markedly induced. Cells isolated by the fluorescence-activated cell sorter simultaneously expressed not only TSHR and NIS proteins but also PAX8 mRNA, an expression pattern unique to thyroid cells and expected in committed thyroid progenitor cells. Such expression continued until d 21 with no influence seen by the addition of TSH or IGF-I. The sequence of gene expression changes observed in these experiments demonstrated the emergence of definitive thyroid endoderm. The activin A induction of thyroid-specific markers, NIS and TSHR, occurred in the absence of TSH stimulation, and, therefore, the emergence of thyroid endoderm in vitro paralleled the emergence of thyroid cells in TSHR-knockout mice. Activin A is clearly a major regulator of thyroid endoderm.
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Thakur, Shilpa, Stephanie Cardenas, and Joanna Klubo-Gwiezdzinska. "The Growth Stimulatory Effects of Thyrotropin and Thyroid Hormones on Thyroid Cancer Depend on Expression of Thyrotropin Receptor and Integrins." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A852—A853. http://dx.doi.org/10.1210/jendso/bvab048.1740.
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Abstract Background: The long-term management of metastatic thyroid cancer (TC) consists of thyrotropin (TSH) suppression with supraphysiologic doses of thyroid hormones (TH) via a negative feedback loop. The goal of TSH suppression is to prevent TSH stimulation of the TSH receptor (TSHR), as it has been shown to promote proliferation of cancer cells. However, TH (T3 and T4) have also been shown to stimulate cancer cell proliferation via αvβ3 integrin signaling. Since both TSH and TH have mitogenic potential, we aimed to investigate which one is a more potent growth stimulus-TSH or TH by analyzing its growth stimulatory effects in TC models. Methods: We analyzed the mRNA expression of TSHR and ITGAV (αv), ITGB3 (β3) integrins in 496 human TC tissue samples, including 65 paired samples of normal tissue (NT) and the corresponding tumor included in The Cancer Genome Atlas (TCGA). We used 13 TC cell lines and analyzed the mRNA expression of 24 genes (4 thyroid-specific genes, 2 TH receptor genes, and 18 integrin genes) with an emphasis on the expression of cell surface receptors αv, β3 integrins, and TSHR. The protein expression of αv, β3, and TSHR was analyzed by immunoblotting. To test the effects of TH and TSH on cell proliferation and expression of αv, β3, and TSHR, cells were treated with varying concentrations of TSH (0.01, 0.1, 1, 10 mIU/mL), T3 (0.1, 1, 10 100 nM) and T4 (1, 10, 100, 1000 nM) for 72 h. Results: Analysis of the RNA seq data from TCGA revealed a significantly higher expression of TSHR in NT compared with TC (log fold change 0.59, p<0.001), lower expression of αv integrin in NT compared with TC (log fold change -0.3, p=0.001), and comparable expression of β3 integrin (log fold change 0.20, p=0.3). Based on the mRNA expression data of 13 TC cell lines, we selected 6 cell lines (FTC133, TPC1, XTC1, OCUT2, C643, THJ16T) characterized by variable αv, β3, and TSHR expression. The TPC1 and OCUT2 cells with high to moderate αVβ3 expression responded to T4 (1000nM; p<0.001) and T3 treatment (100nM; p<0.001) respectively, with increased proliferation, while the cell lines characterized by low to no β3 and/or low αV expression (FTC133, XTC1, C643, and THJ16T) did not change their growth rate in response to TH. The C643 and XTC1 cells characterized by a preserved low-to-moderate TSHR expression responded to TSH treatment (10mIU/mL) with increased proliferation (p<0.05), while the growth curve of cell lines with very low to no TSHR expression (FTC133, TPC1, OCUT1, THJ16T) was not affected. Analysis of the effects of TH and TSH on the mRNA expression of αV, β3, and TSHR was observed to be cell-line specific. Conclusion: The growth stimulatory effects of TSH and TH on TC cells depend on its concentration and expression of TSHR and αVβ3, respectively. Since TC is characterized by relatively lower TSHR and higher αV integrin expression than NT, treatment with supraphysiologic doses of TH in patients with metastatic TC needs to be individualized.
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Ueki, Ikuko, Norio Abiru, Kentaro Kawagoe, and Yuji Nagayama. "Interleukin 10 deficiency attenuates induction of anti-TSH receptor antibodies and hyperthyroidism in a mouse Graves' model." Journal of Endocrinology 209, no. 3 (April 7, 2011): 353–57. http://dx.doi.org/10.1530/joe-11-0129.
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Experimental Graves'-like hyperthyroidism can be induced in susceptible mouse strains by repetitive immunizations with recombinant adenovirus expressing the human full-length TSH receptor (TSHR) or its A-subunit. Previous studies have shown that splenocytes from immunized mice produce interferon (IFN)-γ and interleukin (IL) 10 in response to antigen stimulation in an in vitro T cell recall assay. Although IFN-γ is now well known to be essential for disease induction, the role(s) played by IL10 are unknown. Therefore, this study was conducted to clarify the significance of endogenous IL10 in the pathogenesis of experimental Graves' disease using IL10 deficient (IL10−/−) mice. Our results show that T cell response was augmented when estimated by their antigen-specific secretion of the key cytokine IFN-γ, but B cell function was dampened, that is, anti-TSHR antibody titers were decreased in IL10−/− mice, resulting in a lower incidence of Graves' hyperthyroidism (54% in IL10+/+ vs 25% in IL10−/−). Thus, in addition to IFN-γ, these data clarified the role of IL10 for optimizing anti-TSHR antibody induction and eliciting Graves' hyperthyroidism in our Graves' mouse model.
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Londzin-Olesik, Magdalena, Beata Kos-Kudła, Aleksandra Nowak, and Mariusz Nowak. "The role of oxidative stress in the pathogenesis of Graves’ orbitopathy." Postępy Higieny i Medycyny Doświadczalnej 75 (June 18, 2021): 448–55. http://dx.doi.org/10.5604/01.3001.0014.9482.
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Graves’ disease (GD) is a chronic autoimmune condition in which the anti-thyroid stimulating hormone receptor antibodies (TRAb) activate the thyrotropin receptor (TSHR) located on thyrocytes, leading to excessive thyroid hormone production. TSHR is also expressed in extrathyroidal tissues, in particular, within the orbit. The serum levels of TRAb correlate with the severity and activity of thyroid orbitopathy (TO). TO is the most common extrathyroidal manifestation of GD. It is an autoimmune inflammation of orbital tissues, that is, extraocular muscles, orbital adipose tissue or a lacrimal gland. Increased orbital fibroblast and adipocyte proliferation, overproduction of glycosaminoglycans, as well as extraocular muscle oedema, result in increased orbital tissue volume and trigger the onset of TO symptoms. The pathophysiology of TO is complex and has not been fully unexplained to date. Orbital fibroblasts show expression of the TSHR, which is the main target of autoimmunity. It has been hypothesised that T-cell activation induced by orbital receptor stimulation by the target antibody results in orbital tissue infiltration, triggering a cascade of events which leads to the production of cytokines, growth factors and reactive oxygen species (ROS). ROS cause damage to many components of the cell: the cell membrane through the peroxidation of lipids and proteins leading to a loss of their function and enzymatic activity. Oxidative stress leads to the activation of the antioxidant system, which operates through two mechanisms: enzymatic and non-enzymatic. Assessment of the concentration of oxidative stress markers and the concentration or activity of anti-oxidative system parameters enables the evaluation of oxidative stress severity, which in the future may be utilized to assess treatment efficacy and prognosis in patients with active OT.
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Londzin-Olesik, Magdalena, Beata Kos-Kudła, Aleksandra Nowak, and Mariusz Nowak. "The role of oxidative stress in the pathogenesis of Graves’ orbitopathy." Postępy Higieny i Medycyny Doświadczalnej 75 (January 27, 2021): 1–10. http://dx.doi.org/10.5604/01.3001.0014.6969.
Full textAbstract:
Graves' disease (GD) is a chronic autoimmune condition, in which the anti-thyroid stimulating hormone receptor antibodies (TRAb) activate the thyrotropin receptor (TSHR) located on thyrocytes, leading to excessive thyroid hormone production. TSHR is also expressed in extrathyroidal tissues, in particular, within the orbit. The serum levels of TRAb corelate with severity and activity of thyroid orbitopathy (TO). TO is the most common extrathyroidal manifestation of GD. It is an autoimmune inflammation of orbital tissues, that is, extraocular muscles, orbital adipose tissue or a lacrimal gland. Increased orbital fibroblast and adipocyte proliferation, overproduction of glycosaminoglycans, as well as extraocular muscle oedema result in an increased orbital tissue volume and trigger the onset of TO symptoms. The pathophysiology of TO is complex and has not been fully unexplained to date. Orbital fibroblasts show expression of the TSHR, which is the main target of autoimmunity. It has been hypothesised that T-cell activation induced by orbital receptor stimulation by the target antibody results in orbital tissue infiltration, triggering a cascade of events which leads to the production of cytokines, growth factors and reactive oxygen species (ROS). ROS cause damage to many components of the cell: the cell membrane through the peroxidation of lipids and proteins leading to a loss of their function and enzymatic activity. Oxidative stress leads to activation of the antioxidant system which operates through two mechanisms: enzymatic and non-enzymatic. Assessment of the concentration of oxidative stress markers and the concentration or activity of antioxidative system parameters enables evaluation of oxidative stress severity, which in the future may be utilized for assessment of treatment efficacy and prognosis in patients with active OT.
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Ali, Rejwan, Rauf Latif, Terry Davies, and Mihaly Mezei. "Predicting Transmembrane Dimerization and the Interfaces in Thyroid-Stimulating Hormone Receptor (TSHR) Using Brownian Dynamics Stimulation." Biophysical Journal 100, no. 3 (February 2011): 158a. http://dx.doi.org/10.1016/j.bpj.2010.12.1076.
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Núñez Miguel, R., J. Sanders, D. Y. Chirgadze, J. Furmaniak, and B. Rees Smith. "Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein–protein interactions." Journal of Molecular Endocrinology 42, no. 5 (February 16, 2009): 381–95. http://dx.doi.org/10.1677/jme-08-0152.
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The TSH receptor (TSHR) ligands M22 (a thyroid stimulating human monoclonal antibody) and TSH, bind to the concave surface of the leucine rich repeats domain (LRD) of the TSHR and here, we show that M22 mimics closely the binding of TSH. We compared interactions produced by M22 with the TSHR in the M22–TSHR crystal structure (2.55 Å resolution) and produced by TSH with the TSHR in a TSH–TSHR comparative model. The crystal structure of the TSHR and a comparative model of TSH based on the crystal structure of FSH were used as components to build the TSH–TSHR model. This model was built based on the FSH–FSH receptor structure (2.9 Å) and then the structure of the TSHR in the model was replaced by the TSHR crystal structure. The analysis shows that M22 light chain mimics the TSHβ chain in its interaction with TSHR LRD, while M22 heavy chain mimics the interactions of the TSHα chain. The M22–TSHR complex contains a greater number of hydrogen bonds and salt bridges and fewer hydrophobic interactions than the TSH–TSHR complex, consistent with a higher M22 binding affinity. Furthermore, the surface area formed by TSHR residues N208, Q235, R255, and N256 has been identified as a candidate target region for small molecules which might selectively block binding of autoantibodies to the TSHR.
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Neumann, Susanne, Wenwei Huang, Elena Eliseeva, Steve Titus, Craig J. Thomas, and Marvin C. Gershengorn. "A Small Molecule Inverse Agonist for the Human Thyroid-Stimulating Hormone Receptor." Endocrinology 151, no. 7 (April 28, 2010): 3454–59. http://dx.doi.org/10.1210/en.2010-0199.
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Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1;2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of principle that small, drug-like molecules can inhibit basal signaling by TSHR. We suggest that this small molecule is a lead compound for the development of higher-potency inverse agonists that can be used as probes of TSHR biology with therapeutic potential.
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Neumann, Susanne, Wenwei Huang, Elena Eliseeva, Steve Titus, Craig J. Thomas, and Marvin C. Gershengorn. "A Small Molecule Inverse Agonist for the Human Thyroid-Stimulating Hormone Receptor." Endocrine Reviews 31, no. 3 (June 1, 2010): 403. http://dx.doi.org/10.1210/edrv.31.3.9992.
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ABSTRACT Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1, 2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of principle that small, drug-like molecules can inhibit basal signaling by TSHR. We suggest that this small molecule is a lead compound for the development of higher-potency inverse agonists that can be used as probes of TSHR biology with therapeutic potential.
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Caillou, Bernard, Frédéric Troalen, Eric Baudin, Monique Talbot, Sébastiano Filetti, Martin Schlumberger, and Jean-Michel Bidart. "Na+/I− Symporter Distribution in Human Thyroid Tissues: An Immunohistochemical Study1." Journal of Clinical Endocrinology & Metabolism 83, no. 11 (November 1, 1998): 4102–6. http://dx.doi.org/10.1210/jcem.83.11.5262.
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Antipeptide antibodies raised against the carboxyl-terminal region of the human sodium/iodide (Na+/I−) symporter (hNIS) were used to investigate by immunohistochemistry the presence and distribution of the hNIS protein in normal thyroid tissues, in some pathological nonneoplastic thyroid tissues, and in different histotypes of thyroid neoplasms. In normal thyroid tissue, staining of hNIS protein was heterogeneous and limited to a minority of follicular cells that were in close contact with capillary vessels. In positive cells, immunostaining was limited to the basolateral membrane. In contrast, in Graves’ disease the majority of follicular cells expressed the hNIS protein. In autoimmune thyroiditis, the number of hNIS-positive cells, was similar to that found in normal tissue. These positive cells were found essentially close to lymphocytic infiltrates. This observation supports the concept of hNIS as an autoantigen. In diffuse nodular hyperplasia, hNIS staining was heterogeneous, but the number of hNIS-positive cells exceeded that found in normal tissue. In well differentiated follicular or papillary carcinoma, the number of hNIS-positive cells was significantly lower than in normal tissue. In poorly differentiated follicular carcinoma, the number of hNIS-positive cells was less than that found in well differentiated carcinoma, or there were no positive cells. Interestingly, in all of these thyroid tissues, the number of follicular cells exhibiting TSH receptor (TSHR) immunoreactivity was greater than the number of hNIS-positive cells. As hNIS expression appears to be related to TSHR stimulation, the decreased number of TSHR-positive cells in cancers may contribute to the reduced capacity of neoplastic cells to concentrate iodide. In one patient with a follicular cancer with an absence of hNIS immunostaining, the total body 131I scan showed no uptake in metastatic tissue. In three cancers with positive hNIS cells, the 131I scan showed uptake in lymph node metastases. This suggests that immunodetection of hNIS could predict radioiodine uptake in thyroid cancers.
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Zwermann, O., Y. Suttmann, M. Bidlingmaier, F. Beuschlein, and M. Reincke. "Screening for membrane hormone receptor expression in primary aldosteronism." European Journal of Endocrinology 160, no. 3 (March 2009): 443–51. http://dx.doi.org/10.1530/eje-08-0711.
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ObjectiveThe investigation of expression and functional relevance of G-protein coupled receptors in primary aldosteronism (PA) by molecular and clinical studies.Patients and methodsTissues of 14 aldosterone-producing adenomas (APA), of one unilateral adrenal hyperplasia and of six healthy adult adrenal glands; 12 patients with confirmed PA due to APA; (n=5), idiopathic hyperaldosteronism (n=7) and 8 control subjects (C). The tissues were subjected to a quantitative PCR for determination of mRNA expression levels of AT2R1, GIPR, MC2R, GnRHR, LHR, TRHR, TSHR, glucagon-R, V1aR, V2R, and 5-HT4R. The patients and controls were enrolled in a test protocol consisting of stimulation by posture, mixed meal, ACTH, GnRH, TRH, glucagon, vasopressin, and metoclopramide (MCP). Three patients could be analyzed by both studies. A positive response was defined as an aldosterone increase of more than 50% following stimulation.ResultsAll the tissues revealed AT2R1, MC2R, AVPR, and 5-HT4R mRNA expression. LHR mRNA was found in normal adrenals and 13 adrenal tumors. By contrast with normal adrenals tumorous adrenal tissue expressed GnRHR mRNA (4/15) and TSHR mRNA (1/15). Both the patients and controls responded to posture, ACTH, glucagon, AVP, and MCP. Specific responses were seen in one patient following TRH and three patients following GnRH stimulation.ConclusionsWe provide evidence for peptide hormone responsiveness to various peptide hormones in patients with PA, including GnRH and TRH. A good correlation between clinical and molecular testing could be observed, making an involvement of the receptor expressed in PA possible.
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Latif, R., T. Ando, and T. F. Davies. "Lipid Rafts Are Triage Centers for Multimeric and Monomeric Thyrotropin Receptor Regulation." Endocrinology 148, no. 7 (July 1, 2007): 3164–75. http://dx.doi.org/10.1210/en.2006-1580.
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The TSH receptor (TSHR), a heptahelical G protein-coupled receptor on the surface of thyrocytes, is a major autoantigen and physiological regulator of the thyroid gland. Unlike other G protein-coupled receptors, the TSHR undergoes posttranslational cleavage of its ectodomain, leading to the existence of several forms of the receptor on the plasma membrane. We previously hypothesized that to achieve high fidelity and specificity of TSH ligand or TSHR autoantibody signaling, the TSHR may compartmentalize into microdomains within the plasma membrane. In support of this hypothesis we have shown previously that TSHRs reside in GM1 ganglioside-enriched lipid rafts in the plasma membrane of TSHR-expressing cells. In this study, we further explored the different forms of TSHRs that reside in lipid rafts. We studied both TSHR-transfected cells and rat thyrocytes, using both nondetergent biochemical analyses and receptor-lipid raft colocalization. Using the biochemical approach, we observed that monomeric receptors existed in both raft and nonraft fractions of the cell surface in the steady state. We also demonstrated that the multimeric forms of the receptor were preferentially partitioned into the lipid microdomains. Different TSHR forms, including multimers, were dynamically regulated both by receptor-specific and postreceptor-specific modulators. TSH ligand and TSHR antibody of the stimulating variety induced a decrease of multimeric forms in the raft fractions. In addition, multimeric and monomeric forms of the receptor were both associated with Gsα within and without the rafts. Although failure to achieve total lipid raft disruption prevented a conclusion regarding the relative power of TSHR signaling within and without the raft domains, these data showed clearly that not only were a significant proportion of TSHRs residing within lipid microdomains but that constitutive multimerization of TSHRs was actually regulated within the lipid rafts.
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Neumann, Susanne, Gunnar Kleinau, Stefano Costanzi, Susanna Moore, Jian-kang Jiang, Bruce M. Raaka, Craig J. Thomas, Gerd Krause, and Marvin C. Gershengorn. "A Low-Molecular-Weight Antagonist for the Human Thyrotropin Receptor with Therapeutic Potential for Hyperthyroidism." Endocrinology 149, no. 12 (July 31, 2008): 5945–50. http://dx.doi.org/10.1210/en.2008-0836.
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Low-molecular-weight (LMW) antagonists for TSH receptor (TSHR) may have therapeutic potential as orally active drugs to block stimulating antibodies (TsAbs) in Graves’ hyperthyroidism. We describe an approach to identify LMW ligands for TSHR based on Org41841, a LMW partial agonist for the LH/choriogonadotropin receptor and TSHR. We used molecular modeling and functional experiments to guide the chemical modification of Org41841. We identified an antagonist (NIDDK/CEB-52) that selectively inhibits activation of TSHR by both TSH and TsAbs. Whereas initially characterized in cultured cells overexpressing TSHRs, the antagonist was also active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs in which it inhibited TSH- and TsAb-induced up-regulation of mRNA transcripts for thyroperoxidase. Our results establish this LMW compound as a lead for the development of higher potency antagonists and serve as proof of principle that LMW ligands that target TSHR could serve as drugs in patients with Graves’ disease.
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Milenkovic, Milutin, Xavier De Deken, Ling Jin, Mario De Felice, Roberto Di Lauro, Jacques E. Dumont, Bernard Corvilain, and Francoise Miot. "Duox expression and related H2O2 measurement in mouse thyroid: onset in embryonic development and regulation by TSH in adult." Journal of Endocrinology 192, no. 3 (March 2007): 615–26. http://dx.doi.org/10.1677/joe-06-0003.
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In the thyroid, H2O2 is produced at the apical pole of thyrocytes by one or two NADPH oxidases (NOX), Duox1/2 proteins. The onset of Duox expression was analysed by immunohistochemistry in the developing mouse thyroid in parallel with thyroglobulin (Tg) iodination and the expression of other thyroid differentiation markers. Duox proteins were found at embryonic day (E) 15.5 and were mainly localised at the apical pole of thyrocytes. Tg was detected 1 day before (E14.5) and Tg iodination was concomitant with the expression of both Duox and Na+/I− symporter (NIS; E15.5). The role of TSH in regulating Duox expression and H2O2 accumulation was evaluated in thyroids of adult mice with reduced (Tshrhyt/hyt or mice treated with thyroxine) or increased (methimazole or perchlorate treatment) TSH/Tshr activity. In mice with suppressed TSH/Tshr activity, Duox expression was only partially decreased when compared with wild-type, as observed by western blot. In Tshrhyt/hyt strain, Duox was still expressed at the apical pole and H2O2 measurements were normal. On the other hand, chronic TSH stimulation of the gland led to a decrease of H2O2 measurements without affecting Duox expression. The onset of Duox protein expression is compatible with their proposed function in thyroid hormone synthesis and it can be considered as a functional marker of the developing thyroid. However, Duox expression in adult is much less regulated by TSH than NIS and thyroperoxidase. It is not always correlated with the overall thyroid H2O2 accumulation, highlighting the importance of additional regulatory mechanisms which control either the production or H2O2 degradation.
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Chazenbalk, Gregorio D., Chun-Rong Chen, Sandra M. McLachlan, and Basil Rapoport. "Does Thyrotropin Cleave Its Cognate Receptor?" Endocrinology 145, no. 1 (January 1, 2004): 4–10. http://dx.doi.org/10.1210/en.2003-1002.
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Abstract A recent report of major pathophysiological significance, and opposed to present concepts, is that TSH (but not MS-1, a hamster monoclonal thyroid-stimulating antibody), cleaves the single-chain TSH receptor (TSHR) on the cell surface into its two-subunit form. We reassessed the issue using two approaches. First we wished to confirm the flow-cytometric assay previously used to quantitate TSHR cleavage. We used CHO cell lines expressing large (TSHR-10,000 cells) or conventional (TSHR-0 cells) numbers of TSHR. Cells were preincubated (16 h) in either control medium or medium supplemented with TSH (5 × 10−8m) or MS-1 (10 μg/ml). After stringent washing to maximize removal of residual ligand, we performed flow cytometry with two antibodies, one recognizing only the single-chain TSHR, the other recognizing all (cleaved and uncleaved) TSHRs. TSH pretreatment did not appear to increase TSHR cleavage. Instead we observed ligand occupancy of the TSHR (with MS-1) or fewer receptors on the cell surface (down-regulation), particularly with the TSHR-0 cells. Second, we covalently cross-linked [125I]TSH to monolayers of these cells, an unequivocal method to determine directly the proportion of single-chain and two-subunit TSHR forms. Pretreatment of TSHR-10,000 and TSHR-0 cells with TSH had no effect on the degree of TSHR cleavage. MS-1 slightly reduced spontaneous cleavage. In conclusion, in contrast to a recent report, we show that TSH does not alter the subunit structure of its cognate receptor, and we provide insight into the difficulties associated with the flow-cytometric assay for TSHR cleavage.
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Núñez Miguel, R., J. Sanders, D. Y. Chirgadze, T. L. Blundell, J. Furmaniak, and B. Rees Smith. "FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity." Journal of Molecular Endocrinology 41, no. 3 (July 7, 2008): 145–64. http://dx.doi.org/10.1677/jme-08-0040.
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The crystal structures of the leucine-rich repeat domain (LRD) of the FSH receptor (FSHR) in complex with FSH and the TSH receptor (TSHR) LRD in complex with the thyroid-stimulating autoantibody (M22) provide opportunities to assess the molecular basis of the specificity of glycoprotein hormone–receptor binding. A comparative model of the TSH–TSHR complex was built using the two solved crystal structures and verified using studies on receptor affinity and activation. Analysis of the FSH–FSHR and TSH–TSHR complexes allowed identification of receptor residues that may be important in hormone-binding specificity. These residues are in leucine-rich repeats at the two ends of the FSHR and the TSHR LRD structures but not in their central repeats. Interactions in the interfaces are consistent with a higher FSH-binding affinity for the FSHR compared with the binding affinity of TSH for the TSHR. The higher binding affinity of porcine (p)TSH and bovine (b)TSH for human (h)TSHR compared with hTSH appears not to be dependent on interactions with the TSHR LRD as none of the residues that differ among hTSH, pTSH or bTSH interact with the LRD. This suggests that TSHs are likely to interact with other parts of the receptors in addition to the LRD with these non-LRD interactions being responsible for affinity differences. Analysis of interactions in the FSH–FSHR and TSH–TSHR complexes suggests that the α-chains of both hormones tend to be involved in the receptor activation process while the β-chains are more involved in defining binding specificity.
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Montanelli, Lucia, Joost J. J. Van Durme, Guillaume Smits, Marco Bonomi, Patrice Rodien, Eric J. Devor, Kristin Moffat-Wilson, Leonardo Pardo, Gilbert Vassart, and Sabine Costagliola. "Modulation of Ligand Selectivity Associated with Activation of the Transmembrane Region of the Human Follitropin Receptor." Molecular Endocrinology 18, no. 8 (August 1, 2004): 2061–73. http://dx.doi.org/10.1210/me.2004-0036.
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Abstract Recently, three naturally occurring mutations in the serpentine region of the FSH receptor (FSHr) (D567N and T449I/A) have been identified in three families with spontaneous ovarian hyperstimulation syndrome (OHSS). All mutant receptors displayed abnormally high sensitivity to human chorionic gonadotropin and, in addition, D567N and T449A displayed concomitant increase in sensitivity to TSH and detectable constitutive activity. In the present study, we have used a combination of site-directed mutagenesis experiments and molecular modeling to explore the mechanisms responsible for the phenotype of the three OHSS FSHr mutants. Our results suggest that all mutations lead to weakening of interhelical locks between transmembrane helix (TM)-VI and TM-III, or TM-VI and TM-VII, which contributes to maintaining the receptor in the inactive state. They also indicate that broadening of the functional specificity of the mutant FSHr constructs is correlated to their increase in constitutive activity. This relation between basal activity and functional specificity is a characteristic of the FSHr, which is not shared by the other glycoprotein hormone receptors. It leads to the interesting suggestion that different pathways have been followed during primate evolution to avoid promiscuous stimulation of the TSHr and FSHr by human chorionic gonadotropin. In the hFSHr, specificity would be exerted both by the ectodomain and the serpentine portion.
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Ando, Takao, and Terry F. Davies. "Monoclonal Antibodies to the Thyrotropin Receptor." Clinical and Developmental Immunology 12, no. 2 (2005): 137–43. http://dx.doi.org/10.1080/17402520500078238.
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The thyrotropin receptor (TSHR) is a seven transmembrane G-protein linked glycoprotein expressed on the thyroid cell surface and which, under the regulation of TSH, controls the production and secretion of thyroid hormone from the thyroid gland. This membrane protein is also a major target antigen in the autoimmune thyroid diseases. In Graves' disease, autoantibodies to the TSHR (TSHR-Abs) stimulate the TSHR to produce thyroid hormone excessively. In autoimmune thyroid failure, some patients exhibit TSHR-Abs which block TSH action on the receptor. There have been many attempts to generate human stimulating TSHR-mAbs, but to date, only one pathologically relevant human stimulating TSHR-mAb has been isolated. Most mAbs to the TSHR have been derived from rodents immunized with TSHR antigen from bacteria or insect cells. These antigens lacked the native conformation of the TSHR and the resulting mAbs were exclusively blocking or neutral TSHR-mAbs. However, mAbs raised against intact native TSHR antigen have included stimulating mAbs. One such stimulating mAb has demonstrated a number of differences in its regulation of TSHR post-translational processing. These differences are likely to be reflective of TSHR-Abs seen in Graves' disease.
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Ando, Takao, Rauf Latif, Samira Daniel, Katsumi Eguchi, and Terry F. Davies. "Dissecting Linear and Conformational Epitopes on the Native Thyrotropin Receptor." Endocrinology 145, no. 11 (November 1, 2004): 5185–93. http://dx.doi.org/10.1210/en.2004-0789.
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Abstract The TSH receptor (TSHR) is the primary antigen in Graves’ disease. In this condition, autoantibodies to the TSHR that have intrinsic thyroid-stimulating activity develop. We studied the epitopes on the native TSHR using polyclonal antisera and monoclonal antibodies (mAbs) derived from an Armenian hamster model of Graves’ disease. Of 14 hamster mAbs analyzed, five were shown to bind to conformational epitopes including one mAb with potent thyroid-stimulating activity. Overlapping conformational epitopes were determined by cell-binding competition assays using fluorescently labeled mAbs. We identified two distinct conformational epitopes: epitope A for both stimulating and blocking mAbs and epitope B for only blocking mAbs. Examination of an additional three mouse-derived stimulating TSHR-mAbs also showed exclusive binding to epitope A. The remaining nine hamster-derived mAbs were neutral or low-affinity blocking antibodies that recognized linear epitopes within the TSHR cleaved region (residues 316–366) (epitope C). Serum from the immunized hamsters also recognized conformational epitopes A and B but, in addition, also contained high levels of TSHR-Abs interacting within the linear epitope C region. In summary, these studies indicated that the natively conformed TSHR had a restricted set of epitopes recognized by TSHR-mAbs and that the binding site for stimulating TSHR-Abs was highly conserved. However, high-affinity TSHR-blocking antibodies recognized two conformational epitopes, one of which was indistinguishable from the thyroid-stimulating epitope. Hence, TSHR-stimulating and blocking antibodies cannot be distinguished purely on the basis of their conformational epitope recognition.
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Núñez Miguel, Ricardo, Jane Sanders, Paul Sanders, Stuart Young, Jill Clark, Katarzyna Kabelis, Jane Wilmot, et al. "Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor." Journal of Molecular Endocrinology 49, no. 2 (July 24, 2012): 137–51. http://dx.doi.org/10.1530/jme-12-0040.
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Binding of a new thyroid-stimulating human monoclonal autoantibody (MAb) K1–18 to the TSH receptor (TSHR) leucine-rich domain (LRD) was predicted using charge–charge interaction mapping based on unique complementarities between the TSHR in interactions with the thyroid-stimulating human MAb M22 or the thyroid-blocking human MAb K1–70. The interactions of K1–18 with the TSHR LRD were compared with the interactions in the crystal structures of the M22–TSHR LRD and K1–70–TSHR LRD complexes. Furthermore, the predicted position of K1–18 on the TSHR was validated by the effects of TSHR mutations on the stimulating activity of K1–18. A similar approach was adopted for predicting binding of a mouse thyroid-blocking MAb RSR-B2 to the TSHR. K1–18 is predicted to bind to the TSHR LRD in a similar way as TSH and M22. The binding analysis suggests that K1–18 light chain (LC) mimics binding of the TSH-α chain and the heavy chain (HC) mimics binding of the TSH-β chain. By contrast, M22 HC mimics the interactions of TSH-α while M22 LC mimics TSH-β in interactions with the TSHR. The observed interactions in the M22–TSHR LRD and K1–70–TSHR LRD complexes (crystal structures) with TSH–TSHR LRD (comparative model) and K1–18–TSHR LRD (predictive binding) suggest that K1–18 and M22 interactions with the receptor may reflect interaction of thyroid-stimulating autoantibodies in general. Furthermore, K1–70 and RSR-B2 interactions with the TSHR LRD may reflect binding of TSHR-blocking autoantibodies in general. Interactions involving the C-terminal part of the TSHR LRD may be important for receptor activation by autoantibodies.
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Juiz-Valiña, Paula, María Cordido, Elena Outeiriño-Blanco, Sonia Pértega, Bárbara María Varela-Rodríguez, María Jesús García-Brao, Enrique Mena, Lara Pena-Bello, Susana Sangiao-Alvarellos, and Fernando Cordido. "Central Resistance to Thyroid Hormones in Morbidly Obese Subjects Is Reversed after Bariatric Surgery-Induced Weight Loss." Journal of Clinical Medicine 9, no. 2 (January 28, 2020): 359. http://dx.doi.org/10.3390/jcm9020359.
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Endocrine abnormalities are common in obesity, including altered thyroid function. The altered thyroid function of obesity may be due to a mild acquired resistance to the thyroid hormone. The aim of this study was to investigate the effect of weight loss after bariatric surgery (BS) on resistance to thyroid hormones in patients with extreme obesity compared with a control group. We performed an observational study evaluating patients with extreme obesity who underwent BS. We included 106 patients (83 women) and 38 controls (24 women). The primary endpoint was the thyrotroph thyroxine resistance index (TT4RI) and thyroid stimulating hormone (TSH) index (TSHRI). The parameters were studied before and after surgery. TSHRI and TT4RI were higher in the obese patients than in the control group. TT4RI and TSHI decreased significantly over time after surgery, with this decrease being associated with the excessive body mass index (BMI) loss and C-reactive protein (CRP). In extreme obesity, BS promotes a significant decrease in the increased TT4RI and TSHI. This decrease of TT4RI and TSHI is progressive over time after BS and significantly associated with excess BMI lost and CRP. Extreme obesity is characterized by a mild reversible central resistance to thyroid hormones.
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Kalveram, Kleinau, Szymańska, Scheerer, Rivero-Müller, Grüters-Kieslich, and Biebermann. "The Pathogenic TSH β-subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR." International Journal of Molecular Sciences 20, no. 22 (November 7, 2019): 5564. http://dx.doi.org/10.3390/ijms20225564.
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1) Background: Central congenital hypothyroidism (CCH) is a rare endocrine disorder that can be caused by mutations in the β-subunit of thyrotropin (TSHB). The TSHB mutation C105Vfs114X leads to isolated thyroid-stimulating-hormone-(TSH)-deficiency and results in a severe phenotype. The aim of this study was to gain more insight into the underlying molecular mechanism and the functional effects of this mutation based on two assumptions: a) the three-dimensional (3D) structure of TSH should be modified with the C105V substitution, and/or b) whether the C-terminal modifications lead to signaling differences. 2) Methods: wild-type (WT) and different mutants of hTSH were generated in human embryonic kidney 293 cells (HEK293 cells) and TSH preparations were used to stimulate thyrotropin receptor (TSHR) stably transfected into follicular thyroid cancer cells (FTC133-TSHR cells) and transiently transfected into HEK293 cells. Functional characterization was performed by determination of Gs, mitogen activated protein kinase (MAPK) and Gq/11 activation. 3) Results: The patient mutation C105Vfs114X and further designed TSH mutants diminished cyclic adenosine monophosphate (cAMP) signaling activity. Surprisingly, MAPK signaling for all mutants was comparable to WT, while none of the mutants induced PLC activation. 4) Conclusion: We characterized the patient mutation C105Vfs114X concerning different signaling pathways. We identified a strong decrease of cAMP signaling induction and speculate that this could, in combination with diverse signaling regarding the other pathways, accounting for the patient’s severe phenotype.
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Szkudlinski, Mariusz W., Valerie Fremont, Catherine Ronin, and Bruce D. Weintraub. "Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships." Physiological Reviews 82, no. 2 (April 1, 2002): 473–502. http://dx.doi.org/10.1152/physrev.00031.2001.
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This review focuses on recent advances in the structure-function relationships of thyroid-stimulating hormone (TSH) and its receptor. TSH is a member of the glycoprotein hormone family constituting a subset of the cystine-knot growth factor superfamily. TSH is produced by the pituitary thyrotrophs and released to the circulation in a pulsatile manner. It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs). New insights into the structure-function relationships of TSH permitted better understanding of the role of specific protein and carbohydrate domains in the synthesis, bioactivity, and clearance of this hormone. Recent progress in studies on TSHR as well as studies on the other GPCRs provided new clues regarding the molecular mechanisms of receptor activation. Such advances are a result of extensive site-directed mutagenesis, peptide and antibody approaches, detailed sequence analyses, and molecular modeling as well as studies on naturally occurring gain- and loss-of-function mutations. This review integrates expanding information on TSH and TSHR structure-function relationships and summarizes current concepts on ligand-dependent and -independent TSHR activation. Special emphasis has been placed on TSH domains involved in receptor recognition, constitutive activity of TSHR, new insights into the evolution of TSH bioactivity, and the development of high-affinity TSH analogs. Such structural, physiological, pathophysiological, evolutionary, and therapeutic implications of TSH-TSHR structure-function studies are frequently discussed in relation to concomitant progress made in studies on gonadotropins and their receptors.
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Holthoff, Hans-Peter, Kerstin Uhland, Gabor Laszlo Kovacs, Andreas Reimann, Kristin Adler, Clara Wenhart, and Martin Ungerer. "Thyroid-stimulating hormone receptor (TSHR) fusion proteins in Graves’ disease." Journal of Endocrinology 246, no. 2 (August 2020): 135–47. http://dx.doi.org/10.1530/joe-20-0061.
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Graves’ disease is an autoimmune disorder, which is characterized by stimulatory antibodies targeting the human thyrotropin receptor (TSHR), resulting in hyperthyroidism and multiple organ damage. We systematically investigated monomeric and dimeric fusion proteins of the A subunit of TSHR for efficacy to bind to the monoclonal patient antibody M22, to interact with Graves’ patient serum samples, and to impact on anti-TSHR antibody titers, hyperthyroidism, tachycardia and other in vivo read-outs in a long-term mouse model of Graves’ disease induced by immunization with a recombinant adenovirus encoding TSHR A. Binding assays and functional measurements of TSHR-dependent cAMP formation showed binding of monomeric TSHR-His and dimeric TSHR-Fc to the anti-TSHR antibody M22 at low-effective concentrations (EC50 of 5.7 nmol/L and 8.6 nmol/L) and inhibition of the effects of this antibody at high efficiencies (IC50 values of 16–20 nmol/L). Both proteins also block the effects of polyclonal anti-TSHR antibodies occurring in Graves’ patient sera with somewhat lower average efficiencies (mean IC50 values of 29 nmol/L and 68 nmol/L). However, in vivo characterization of epicutaneous patch administrations of TSHR-Fc at doses of 0.3 and 0.6 mg/kg body weight in a murine Graves’ disease model did not result in any improvement of disease parameters. In conclusion, high affinity binding of TSHR-Fc to pathological anti-TSHR antibodies was not matched by efficacy to improve Graves’ disease parameter in a long-term mouse model.
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van Rosmalen, Laura, Jayme van Dalum, David G. Hazlerigg, and Roelof A. Hut. "Gonads or body? Differences in gonadal and somatic photoperiodic growth response in two vole species." Journal of Experimental Biology 223, no. 20 (September 11, 2020): jeb230987. http://dx.doi.org/10.1242/jeb.230987.
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ABSTRACTTo optimally time reproduction, seasonal mammals use a photoperiodic neuroendocrine system (PNES) that measures photoperiod and subsequently drives reproduction. To adapt to late spring arrival at northern latitudes, a lower photoperiodic sensitivity and therefore a higher critical photoperiod for reproductive onset is necessary in northern species to arrest reproductive development until spring onset. Temperature–photoperiod relationships, and hence food availability–photoperiod relationships, are highly latitude dependent. Therefore, we predict PNES sensitivity characteristics to be latitude dependent. Here, we investigated photoperiodic responses at different times during development in northern (tundra or root vole, Microtus oeconomus) and southern vole species (common vole, Microtus arvalis) exposed to constant short (SP) or long photoperiod (LP). Although the tundra vole grows faster under LP, no photoperiodic effect on somatic growth is observed in the common vole. In contrast, gonadal growth is more sensitive to photoperiod in the common vole, suggesting that photoperiodic responses in somatic and gonadal growth can be plastic, and might be regulated through different mechanisms. In both species, thyroid-stimulating hormone β-subunit (Tshβ) and iodothyronine deiodinase 2 (Dio2) expression is highly increased under LP, whereas Tshr and Dio3 decrease under LP. High Tshr levels in voles raised under SP may lead to increased sensitivity to increasing photoperiods later in life. The higher photoperiodic-induced Tshr response in tundra voles suggests that the northern vole species might be more sensitive to thyroid-stimulating hormone when raised under SP. In conclusion, species differences in developmental programming of the PNES, which is dependent on photoperiod early in development, may form different breeding strategies as part of latitudinal adaptation.
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Nakahara, Mami, Norisato Mitsutake, Hikaru Sakamoto, Chun-Rong Chen, Basil Rapoport, Sandra M. McLachlan, and Yuji Nagayama. "Enhanced Response to Mouse Thyroid-Stimulating Hormone (TSH) Receptor Immunization in TSH Receptor-Knockout Mice." Endocrinology 151, no. 8 (June 16, 2010): 4047–54. http://dx.doi.org/10.1210/en.2010-0315.
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Graves-like hyperthyroidism is induced in BALB/c mice by immunization with adenovirus expressing the human TSH receptor (TSHR) A-subunit (amino acids 1–289). However, because of nonidentity between the human and mouse TSHR (∼87% amino acid homology), we compared the responses of mice immunized with adenoviruses expressing either the mouse or the human TSHR A-subunit. Wild-type (wt) BALB/c mice immunized with the mouse A-subunit developed neither TSHR antibodies (measured by flow cytometry) nor thyroid lymphocytic infiltration. However, wt C57BL/6 mice developed sparse intrathyroidal lymphocyte infiltration without antibody production. Depletion of naturally occurring regulatory CD4+CD25+ T cells had little effect. These results indicate the inability to break tolerance to the mouse TSHR in wt mice. In contrast, TSHR knockout (KO) BALB/c mice generated mouse TSHR antibodies in response to mouse A-subunit immunization and augmented human TSHR antibody response to human A-subunit immunization. Thyroid-stimulating antibody titers measured in a functional bioassay were comparable in human A-subunit immunized wt mice and in TSHR KO mice immunized with either the mouse or human A-subunit. In conclusion, immune response to the mouse TSHR is readily induced in TSHR KO but not in wt mice. Only in the former does immunization with adenovirus expressing the mouse A-subunit generate antibodies capable of activating the mouse TSHR. TSHR KO mice are, therefore, of value for future studies dissecting the autoimmune response to the mouse TSHR.
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Decroli, Eva, and Alexander Kam. "Dampak Klinis Thyroid-Stimulating Hormone." Jurnal Kesehatan Andalas 6, no. 1 (July 20, 2017): 222. http://dx.doi.org/10.25077/jka.v6i1.674.
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Thyroid-Stimulating Hormone (TSH), yang disebut juga dengan tirotropin, adalah glikoprotein yang disekresikan oleh bagian anterior dari kelenjar hipofisis. Sintesis dan sekresi dari TSH diatur oleh faktor dari hipotalamus yang didominasi oleh thyrotropin-releasing hormone (TRH) dan faktor perifer yang didominasi oleh kadar hormon tiroid. Setelah disintesis, TSH disekresikan, lalu akan berikatan dengan reseptor yang disebut Thyroid-Stimulating Hormone Receptor (TSHR). Ikatan TSH-TSHR akan memberikan dampak klinis terhadap jaringan dan organ tempat terjadinya ikatan tersebut. Ikatan tersebut bisa terjadi pada kelenjar tiroid dan jaringan ekstratiroid. Jaringan yang sudah dikenal mengekspresikan TSHR adalah jaringan adiposa, hipotalamus, hipofisis anterior, tulang, hati dan sistem imun.
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Revekka, Gyftaki, Liacos Christina, Politi Ekaterini, Liontos Michalis, Saltiki Katerina, Papageorgiou Theocharis, Thomakos Nikolaos, et al. "Differential Transcriptional and Protein Expression of Thyroid-Stimulating Hormone Receptor in Ovarian Carcinomas." International Journal of Gynecologic Cancer 24, no. 5 (June 2014): 851–56. http://dx.doi.org/10.1097/igc.0000000000000139.
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ObjectiveThyroid-stimulating hormone (TSH) regulates normal thyroid function by binding to its receptor (thyroid-stimulating hormone receptor -TSHR) that is expressed at the surface of thyroid cells. Recently, it has been demonstrated that TSHR is abundantly expressed in several tissues apart from the thyroid, among them the normal ovarian surface epithelium. The role of TSHR expression outside the thyroid is not completely understood. The current study examines possible alterations of TSHR expression in ovarian carcinomas and its implication in ovarian carcinogenesis.Materials and MethodsQuantitative real-time polymerase chain reaction and immunohistochemistry analysis of TSHR expression were performed in 34 ovarian carcinoma specimens and 10 normal ovarian tissues (controls).ResultsSignificant reduction in TSHR messenger RNA (mRNA) expression was detected in ovarian carcinomas (mean [SD]: 0.518 [0.0934] vs normal, 49.4985 [89.1626];P< 0.001, Mann-WhitneyUtest), whereas TSHR protein levels were significantly increased (percentage of positive cells: cancer, 73.55% [20.09%], vs normal, 54.54% [21.14%]; intensity: cancer, 2.52 [0.508], vs normal 1 [0];P= 0.012, Mann-WhitneyUtest). No significant differences in TSHR mRNA were found according to history of thyroid disease.ConclusionsOur study describes for the first time alterations in TSHR expression both at mRNA and protein levels in ovarian carcinomas. The discrepancy between the decreased levels of the TSHR mRNA and the increased protein expression has already been described in thyroid carcinomas and might be due to alterations in its degradation by the ubiquitin system or other unknown mechanisms. Further analysis could elucidate the role of these findings in ovarian carcinogenesis.
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Kroschinsky, Frank, Karsten Conrad, Kirsten Poppe-Thiede, Rainer Ordemann, Andrea Schlaupitz, Gabi Rall, Claudia Rutt, and Gerhard Ehninger. "Is There a Risk in Allogeneic PBPC Donation for Autoimmune Diseases Due to Short-Term Treatment with rhG-CSF? Preliminary Results of a Prospective Study in 100 Unrelated Stem Cell Donors." Blood 104, no. 11 (November 16, 2004): 2190. http://dx.doi.org/10.1182/blood.v104.11.2190.2190.
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Abstract Short-term administration of rhG-CSF is a safe and effective procedure for mobilization of allogeneic PBPC in healthy related and unrelated donors. Mild to moderate bone pain is the main side effect occurring in about 80 % of donors, whereas major complications are extremely rare. Recently we observed a patient, who developed life-threatening autoimmune hyperthyreoidism two weeks after rhG-CSF stimulated unrelated PBPC donation (Kroschinsky et al., Haematologica 2004). Anecdotal reports in the literature describe thyroid dysfunction in cancer patients who received rhG-CSF or rhGM-CSF to enhance neutrophil recovery after chemotherapy. In patients with autoimmune disorders who had been treated with rhG-CSG for secondary neutropenia a flare up of disease specific symptoms was observed. Although the current evidence is poor, there might be a potential role of rhG-CSF in thyroid dysfunction and autoimmunity due to its pleotropic effects on different types of cellular and humoral immune effectors. Therefore we prospectively investigated 104 (27 female, 77 male, median age 36 yrs) unrelated PBPC donors for organ and tissue specific autoantibodies. Mobilization treatment consisted of 7.5 μg/kg body weight lenograstim (Granocyte™, Chugai Pharma Inc., Tokyo, Japan) for five days. Leukaphereses were performed on day 5 and 6. Blood samples were taken at pre-donation health-check (before rhG-CSF stimulation, sample 1), at day of apheresis (sample 2) and four weeks after donation (sample 3). The panel of 21 autoantibodies which was tested sequentially is listed in the table. The frequency of positive findings varied considerably between the different antibody specificities. Whereas none of the donors showed reactivity for antibodies to LKM-1, insulin or proteinase-3, antibodies to endothelial antigens were detected before, at and after donation in 16.5, 13.4 and 17.9 % of donors, respectively. No significant differences were found comparing the number of positive results of the sequential antibody testing. However, there was a significant increase in antibody concentrations measured by immunoassays from sample 1 to sample 3 for anti-TSHR (p=0.02), anti-PR3 (p<0.001) and anti-INS (p=0.001). In contrast concentration of cardiolipin antibodies decrease significantly (IgM p=0.014, IgG p=0.01). These preliminary results give no evidence for a risk of allogeneic PBPC donors to develop autoimmunity due to rhG-CSF treatment. However there might be a modulatory impact in some antibody specificities which are on further investigation. Autoantibodies and assays Immunofluorescence Enzyme- or Radioimmunoassay Smooth muscle ab (SMA) Cardiolipin ab (aCL) Parietal cell ab (PCA) Phosphatidylserin ab (APSA) Antinuclear ab (ANA) Ab to insulin (INS) Antineutrophil cytoplasmic ab(pANCA, cANCA) Ab to Ro60-Sjogren’s syndrome antigen (Ro/SSA) Islet cells ab (ICA) Thyroid ab (anti-TG, anti-TPO, anti-TSHR) Ab targeting endothelial cells (AECA, KE) Ab to myeloperoxidase (MPO) Liver/kidney microsomal ab (LKM-1) Ab to proteinase-3 (PR-3) Ab to soluble liver antigen (SLA/ LP) Ab to insulin (INS) Smooth muscle ab (SMA) Cardiolipin ab (aCL)
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Chu, Yu-De, and Chau-Ting Yeh. "The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells." Cells 9, no. 7 (July 20, 2020): 1730. http://dx.doi.org/10.3390/cells9071730.
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The thyroid stimulating hormone (TSH) and its cognate receptor (TSHR) are of crucial importance for thyrocytes to proliferate and exert their functions. Although TSHR is predominantly expressed in thyrocytes, several studies have revealed that functional TSHR can also be detected in many extra-thyroid tissues, such as primary ovarian and hepatic tissues as well as their corresponding malignancies. Recent advances in cancer biology further raise the possibility of utilizing TSH and/or TSHR as a therapeutic target or as an informative index to predict treatment responses in cancer patients. The TSH/TSHR cascade has been considered a pivotal modulator for carcinogenesis and/or tumor progression in these cancers. TSHR belongs to a sub-group of family A G-protein-coupled receptors (GPCRs), which activate a bundle of well-defined signaling transduction pathways to enhance cell renewal in response to external stimuli. In this review, recent findings regarding the molecular basis of TSH/TSHR functions in either thyroid or extra-thyroid tissues and the potential of directly targeting TSHR as an anticancer strategy are summarized and discussed.
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Bell, Andrea, Annemarie Gagnon, Laura Grunder, Sonia J. Parikh, Terry J. Smith, and Alexander Sorisky. "Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts." American Journal of Physiology-Cell Physiology 279, no. 2 (August 1, 2000): C335—C340. http://dx.doi.org/10.1152/ajpcell.2000.279.2.c335.
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Controversy continues about whether, and to what levels of abundance, thyroid-stimulating hormone receptors (TSHR) are found in human tissues other than the thyroid gland. Restricted expression to the thyroid and orbit would suggest that TSHR represents the target autoantigen in thyroid-associated ophthalmopathy. A more generalized pattern of tissue expression would be inconsistent with TSHR acting as the autoantigen that is solely responsible for selectively targeting the immune system to the orbit. We have detected TSHR mRNA in human abdominal adipose tissue by Northern blot analysis. TSHR protein was also detected, by immunoblotting with two different antibodies, in preadipocytes isolated from human abdominal subcutaneous and omental adipose tissue and in derivative adipocytes differentiated in primary culture. Preadipocytes treated with thyroid-stimulating hormone (TSH) exhibited a sevenfold increase in the activity of p70 S6 kinase, a serine/threonine kinase recently recognized as a downstream target of TSHR in thyroid cells. Activation of p70 S6 kinase by TSH was also observed in orbital fibroblasts. Thus TSHR protein expression is found in fibroblasts from several anatomic locations, suggesting that factors other than site-limited TSHR expression must be involved in restricting the distribution of Graves' disease manifestations. Furthermore, the presence of functional TSHR in preadipocytes raises the possibility of a novel role for TSHR signaling in adipose tissue development.
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Diana, Tanja, Paul Olivo, and George Kahaly. "Thyrotropin Receptor Blocking Antibodies." Hormone and Metabolic Research 50, no. 12 (October 4, 2018): 853–62. http://dx.doi.org/10.1055/a-0723-9023.
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AbstractAutoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be done either via competitive-binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity. Historically bioassays for anti-TSHR-Ab were research tools and were used to study the pathophysiology of Graves’ disease and Hashimoto’s thyroiditis. In the past, bioassays for anti-TSHR-Abs were laborious and time-consuming and varied widely in performance from laboratory to laboratory. Recent advances in the development of cell-based assays, including the application of molecular engineering, have led to significant improvements that have enabled bioassays to be employed routinely in clinical laboratories. The prevalence and functional significance of TSHR blocking autoantibodies (TBAb) in autoimmune hypothyroidism has been less well investigated compared to TSHR stimulating Ab. There is an increasing body of data, however, that demonstrate the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with AITD. In the present review, we summarize the different methods used to measure TBAb, and discuss their prevalence and clinical relevance.
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Ahn, Moon Bae. "Extrathyroidal Manifestations of Persistent Sporadic Non-Autoimmune Hyperthyroidism in a 6-Year-Old Boy: A Case Report." Life 11, no. 7 (July 19, 2021): 713. http://dx.doi.org/10.3390/life11070713.
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Thyroid-stimulating hormone receptor (TSHR) belongs in a subfamily of the G protein-coupled receptors. Thyroid-stimulating hormone receptor gene (TSHR), a gene encoding TSHR, is a major controller of thyroid cell metabolism, and its gain of function mutation leads to non-autoimmune hyperthyroidism (NAH), a condition of a prolonged state of hyperthyroidism. Diverse human diseases, and genetic, constitutional, or environmental factors contribute to the phenotypic variations of TSHR mutations; however, the underlying mechanisms leading to various extrathyroidal manifestations across ages are poorly understood. In 2018, the first Korean case of persistent sporadic NAH due to missense mutation of TSHR was reported, and this report highlights the extrathyroidal manifestations of NAH. Further investigation is warranted to clarify the roles of functional mutations of TSHR by investigating the correlation between G protein-dependent signaling properties and clinical phenotypes associated with persistent hyperthyroidism in order to develop novel therapies that could be provided for numerous conditions caused by NAH.
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Morshed, Syed A., Rauf Latif, and Terry F. Davies. "Characterization of Thyrotropin Receptor Antibody-Induced Signaling Cascades." Endocrinology 150, no. 1 (August 21, 2008): 519–29. http://dx.doi.org/10.1210/en.2008-0878.
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The TSH receptor (TSHR) is constitutively active and is further enhanced by TSH ligand binding or by stimulating TSHR antibodies (TSHR-Abs) as seen in Graves’ disease. TSH is known to activate the thyroid epithelial cell via both Gαs-cAMP/protein kinase A/ERK and Gαq-Akt/protein kinase C coupled signaling networks. The recent development of monoclonal antibodies to the TSHR has enabled us to investigate the hypothesis that different TSHR-Abs may have unique signaling imprints that differ from TSH ligand itself. We have, therefore, performed sequential studies, using rat thyrocytes (FRTL-5, passages 5–20) as targets, to examine the signaling pathways activated by a series of monoclonal TSHR-Abs in comparison with TSH itself. Activation of key signaling molecules was estimated by specific immunoblots and/or enzyme immunoassays. Continuing constitutive TSHR activity in thyroid cells, deprived of TSH and serum for 48 h, was demonstrated by pathway-specific chemical inhibition. Under our experimental conditions, TSH ligand and TSHR-stimulating antibodies activated both Gαs and Gαq effectors. Importantly, some TSHR-blocking and TSHR-neutral antibodies were also able to generate signals, influencing primarily the Gαq effectors and induced cell proliferation. Most strikingly, antibodies that used the Gαq cascades used c-Raf-ERK-p90RSK as a unique signaling cascade not activated by TSH. Our study demonstrated that individual TSHR-Abs had unique molecular signatures which resulted in sequential preferences. Because downstream thyroid cell signaling by the TSHR is both ligand dependent and independent, this may explain why TSHR-Abs are able to have variable influences on thyroid cell biology. Antibodies to the TSH receptor produce unique signaling imprints which differ from its ligand, indicating that these antibodies have variable effects on thyroid cell biology.