Thyrotropin receptor, still much to be learned from the patients

Briet, Claire; Suteau, Valentine; Munier, Mathilde; Rodien, Patrice

doi:10.1016/j.beem.2018.03.002

Cited by 14 publications

(17 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Single point constitutively activating mutations (CAM) in the transition of LRRD to hinge region on the converging helix (CH) and in the extracellular loops (ECL) of TSHR showed synergistic effects in their combinations as multiple mutations and cooperatively trigger the signal (Kleinau et al, 2008). These and many other CAM [collected in GPHR research resource: www.ssfa-gphr.de (Kreuchwig et al, 2013)] support the hypothesis that the hinge region interacts with the ECL constraining the basal state, which is released/changed upon activation [FSHR reviewed in depth by Briet et al (2018)].…”

Section: Introductionmentioning

confidence: 96%

Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

Marcinkowski

Kreuchwig

Mendieta

et al. 2019

Molecular Pharmacology

View full text Add to dashboard Cite

The large TSH-bound ectodomain of the thyrotropin receptor (TSHR) activates the transmembrane domain (TMD) indirectly via an internal agonist (IA). The ectodomain/TMD interface consists of a converging helix, a Cys-Cys-bridge-linked IA, and extracellular loops (ECL). To investigate the intramolecular course of molecular activation, especially details of the indirect activation, we narrowed down allosteric inhibition sites of negative allosteric modulator (NAM) by mutagenesis, homology modeling, and competition studies with positive allosteric modulator (PAM). From the inhibitory effects of NAM S37a on: 1) chimeras with swapped ectodomain, 2) stepwise N-terminal truncations, 3) distinct constitutively active mutations distributed across the hinge region and ECL, but not across the TMD, we conclude that S37a binds at the ectodomain/TMD interface, between the converging helix, ECL1, and the IA. This is also supported by the noncompetitive inhibition of PAM-C2-activation by S37a in the TSHR-TMD construct lacking the ectodomain. Mutagenesis studies on the IA and ECL were guided by our refined model of the ectodomain/TMD interface and indicate an interaction with the TSHR-specific residues E404 (preceding IA) and H478 (ECL1). At this new allosteric interaction site, NAM S37a blocks both TSH-and PAM-induced activation of the TSHR. Our refined models, mutations, and new allosteric binding pocket helped us to gain more detailed insights into the intramolecular course of TSHR activation at the ectodomain/TMD interface, including the delocalization of the converging helix and rearrangement of the conformation of IA. These changes are embedded between the ECL and cooperatively trigger active conformations of TMD. SIGNIFICANCE STATEMENT The intramolecular activation mechanisms of the TSHR appear to be distinct from those of other G protein-coupled receptors, as the TSHR has a uniquely large N-terminal ectodomain that includes the hormone binding site and an internal agonist sequence. We present new molecular and structural insights into the interface between ectodomain and transmembrane domain in the TSHR, as well as the transfer of activation to the transmembrane domain. This knowledge is critical for understanding activation or inhibition of the receptor by allosteric ligands. We have identified a new allosteric antagonist binding pocket that is located exactly at this interface and possesses specific features that may allow the generation of potent highly TSHR-selective drugs, of potential value for the treatment of Graves' orbitopathy.

show abstract

Section: Introductionmentioning

confidence: 96%

Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

Marcinkowski

Kreuchwig

Mendieta

et al. 2019

Molecular Pharmacology

View full text Add to dashboard Cite

show abstract

“…The design of our study limits our possibilities to conclude whether observed visfatin changes during recovery in hyperthyroid females simply reflect increase of adiposity or is a compensatory response involved in glucose regulation. On the other hand, since TSH receptor is expressed in adipocytes, observed changes might result from TSH receptor stimulation in fat tissue potentially leading to release of visfatin (28). In contrast to other authors, visfatin remained unchanged after recovery in hypothyroid women (9).…”

Section: Discussionmentioning

confidence: 63%

Does euthyroid mean healthy? Effect of restoration of thyroid function on body composition, insulin resistance and visfatin concentrations in women with hypo- and hyperthyroidism.

Sawicka‐Gutaj

Zybek-Kocik

Kloska

et al. 2020

Preprint

View full text Add to dashboard Cite

Background We aimed to investigate the effect of restoration of euthyroidism on serum visfatin in severe thyroid dysfunction, and its associations with insulin resistance and body composition. Methods This was an observational study with consecutive enrollment. We included females newly diagnosed with overt hypo- or hyperthyroidism caused by autoimmune thyroid diseases. Laboratory parameters and body composition analysis were assessed before and after the therapy. Results Initially, 105 females were enrolled: 49 hyperthyroid (median age of 34 years) and 44 hypothyroid (median age of 46) completed the study. In the hyperthyroid group, visfatin levels increased (< 0.0001), while glucose levels decreased (< 0.0001). Total body mass and fat mass in the trunk and limbs significantly increased during the treatment. In the hypothyroid group, significant weight loss resulted from decrease of fat and muscle masses in trunk and limbs. Visfatin serum concentrations positively correlated with total fat mass(r = 0.19,p = 0.01) and insulin levels(r = 0.17,p = 0.0.18). Conclusions We may conclude that restoration of thyroid function is not associated with beneficial changes in body composition, especially among hyperthyroid females, reflected by the significant increase of fat mass followed by the increase of circulating visfatin concentrations.

show abstract

“…Furthermore, TSH receptor (TSHR) expression was found in several extrathyroidal organs and tissues, mainly in adipose tissue, bones and liver. TSHR stimulation in adipocytes activates protein kinases A and C leading to lipolysis, as well as to release of interkleukin-6 and monocyte chemoattractant protein 1 (MCP-1) [30,31]. Also, TSHR mRNA expression was detected in peripheral blood, with potential clinical significance in patients with papillary thyroid cancers [32].…”

Section: Discussionmentioning

confidence: 99%

Determinants of Visfatin/NAMPT Serum Concentration and its Leukocyte Expression in Hyperthyroidism

et al. 2018

View full text Add to dashboard Cite

We aimed to analyze the potential influence of thyroid autoimmunity on visfatin/NAMPT serum concentration and its leukocyte expression in hyperthyroid patients. This is a single-center, cross-sectional study with consecutive enrollment. All patients with newly diagnosed overt hyperthyroidism in a course of Graves' disease or toxic nodular goiter were included in the study. They underwent physical examination, laboratory investigation, body composition analysis, and thyroid ultrasound. mRNA leukocyte expressions were measured using RT-qPCR. Of the 173 patients, 95 were enrolled in further analysis [67 patients with Graves' disease (GD) and 28 with toxic nodular goiter (TNG)]. Control group consisted of 43 healthy volunteers adjusted for age, sex, and BMI. Higher NAMPT/visfatin serum concentration was found in patients with GD comparing with patients with TNG (p=0.03855). We found significant leukocyte overexpression in GD patients (n=32) as compared to TNG patients (n=18) and euthyroid controls (n=24) (p=0.005965). Simple linear regression analysis revealed that NAMPT/visfatin serum concentration was significantly associated with leukocyte expression, thyroid autoimmunity, age, HOMA-IR, and fat mass percentage (FM%). leukocyte expression was related to thyroid autoimmunity, age, and TRAb levels. The stepwise multiple regression analysis revealed FM% and HOMA-IR as independent predictors of visfatin/NAMPT serum levels. In a separate stepwise multiple regression analysis, we confirmed the association between leukocyte expression and TRAb levels. We found that fat mass percentage together with HOMA-IR are the most significant predictors of visfatin/NAMPT serum elevation in hyperthyroid patients.

show abstract

Thyrotropin receptor, still much to be learned from the patients

Cited by 14 publications

References 95 publications

Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

Thyrotropin Receptor: Allosteric Modulators Illuminate Intramolecular Signaling Mechanisms at the Interface of Ecto- and Transmembrane Domain

Does euthyroid mean healthy? Effect of restoration of thyroid function on body composition, insulin resistance and visfatin concentrations in women with hypo- and hyperthyroidism.

Determinants of Visfatin/NAMPT Serum Concentration and its Leukocyte Expression in Hyperthyroidism

Contact Info

Product

Resources

About