Susanne Neumann

Publications (66) View all

• Source

  Available from: Susanne Neumann

  Article: Novel Insights on Thyroid Stimulating Hormone Receptor Signal Transduction.

  Gunnar Kleinau, Susanne Neumann, Annette Grüters, Heiko Krude, Heike Biebermann
  [show abstract] [hide abstract]
  ABSTRACT: The thyrotropin or thyroid stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-family of family A G-protein coupled receptors (GPCRs). The TSHR is of great importance for the growth and function of the thyroid gland. The TSHR and its endogenous ligand TSH are pivotal proteins with respect to a variety of physiological functions and malfunctions. The molecular events of TSHR regulation can be summarized as a process of signal transduction, including signal reception, conversion and amplification. The steps during signal transduction from the extra- to the intracellular sites of the cell are not yet comprehensively understood. However, essential new insights have been achieved in recent years on the interrelated mechanisms at the extracellular region, the transmembrane domain and intracellular components. This review contains a critical summary of available knowledge of the molecular mechanisms of signal transduction at the TSHR, for example, the key amino acids involved in hormone binding or in the structural conformational changes that lead to G-protein activation or signaling regulation. Aspects of TSHR oligomerization, signaling promiscuity, signaling selectivity, phenotypes of genetic variations and potential extra-thyroidal receptor activity are also considered, as these are relevant to an understanding of the overall function of the TSHR, including physiological, pathophysiological and pharmacological perspectives. Directions for future research are discussed.
  Endocrine reviews 05/2013; · 19.76 Impact Factor
• Article: A Small Molecule Antagonist Inhibits Thyrotropin Receptor Antibody-Induced Orbital Fibroblast Functions Involved in the Pathogenesis of Graves Ophthalmopathy.

  Adina F Turcu, Seema Kumar, Susanne Neumann, Michael Coenen, Seethalakshmi Iyer, Pamela Chiriboga, Marvin C Gershengorn, Rebecca S Bahn
  [show abstract] [hide abstract]
  ABSTRACT: Context:Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction.Objective:The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH).Design:Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling.Main Outcome Measures:cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed.Results:Compound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production.Conclusions:Because cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.
  The Journal of clinical endocrinology and metabolism 03/2013; · 6.50 Impact Factor
• Source

  Available from: Susanne Neumann

  Article: Update in TSH Receptor Agonists and Antagonists.

  Marvin C Gershengorn, Susanne Neumann
  [show abstract] [hide abstract]
  ABSTRACT: The physiological role of the TSH receptor (TSHR) as a major regulator of thyroid function is well understood, but TSHRs are also expressed in multiple normal extrathyroidal tissues, and the physiological roles of TSHRs in these tissues are unclear. Moreover, TSHRs play a major role in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Small molecule, "drug-like" TSHR agonists, neutral antagonists, and inverse agonists may be useful as probes of TSHR function in extrathyroidal tissues and as leads to develop drugs for several diseases of the thyroid. In this Update, we review the most recent findings regarding the development and use of these small molecule TSHR ligands.
  The Journal of clinical endocrinology and metabolism 09/2012; · 6.50 Impact Factor
• Article: A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves' orbital fibroblasts.

  Susanne Neumann, Arthur Pope, Elizabeth Geras-Raaka, Bruce M Raaka, Rebecca S Bahn, Marvin C Gershengorn
  [show abstract] [hide abstract]
  ABSTRACT: Fibroblasts (FIBs) within the retro-orbital space of patients with Graves' disease (GOFs) express thyrotropin receptors (TSHRs) and are thought to be an orbital target of TSHR-stimulating autoantibodies in Graves' ophthalmopathy (GO). Recently, we developed a low molecular weight, drug-like TSHR antagonist (NCGC00229600) that inhibited TSHR activation in a model cell system overexpressing TSHRs and in normal human thyrocytes expressing endogenous TSHRs. Herein, we test the hypothesis that NCGC00229600 will inhibit activation of TSHRs endogenously expressed in GOFs. Three strains of GOFs, previously obtained from patients with GO, were studied as undifferentiated FIBs and after differentiation into adipocytes (ADIPs), and another seven strains were studied only as FIBs. ADIP differentiation was monitored by morphology and measurement of adiponectin mRNA. FIBs and ADIPs were treated with the TSH- or TSHR-stimulating antibody M22 in the absence or presence of NCGC00229600 and TSHR activation was monitored by cAMP production. FIBs contained few if any lipid vesicles and undetectable levels of adiponectin mRNA, whereas ADIPs exhibited abundant lipid vesicles and levels of adiponectin mRNA more than 250,000 times greater than FIBs; TSHR mRNA levels were 10-fold higher in ADIPs than FIBs. FIBs exhibited higher absolute levels of basal and forskolin-stimulated cAMP production than ADIPs. Consistent with previous findings, TSH stimulated cAMP production in the majority of ADIP strains and less consistently in FIBs. Most importantly, NCGC00229600 reduced both TSH- and M22-stimulated cAMP production in GOFs. These data confirm previous findings that TSHR activation may cause increased cAMP production in GOFs and show that NCGC00229600 can inhibit TSHR activation in GOFs. These findings suggest that drug-like TSHR antagonists may have a role in treatment of GO.
  Thyroid: official journal of the American Thyroid Association 07/2012; 22(8):839-43. · 2.60 Impact Factor
• Article: A Drug-like Antagonist Inhibits TSH Receptor-Mediated Stimulation of cAMP Production in Graves' Orbital Fibroblasts.

  Marvin C Gershengorn, Susanne Neumann, Arthur Pope, Elizabeth Geras-Raaka, Bruce M Raaka, Rebecca S Bahn
  [show abstract] [hide abstract]
  ABSTRACT: Background: Fibroblasts within the retro-orbital space of patients with Graves' disease (GOFs) express TSH receptors (TSHRs) and are thought to be an orbital target of TSHR-stimulating autoantibodies in Graves' ophthalmopathy (GO). Recently, we developed a low molecular weight, drug-like TSHR antagonist (NCGC00229600) that inhibited TSHR activation in a model cell system over-expressing TSHRs and in normal human thyrocytes expressing endogenous TSHRs. Herein, we test the hypothesis that NCGC00229600 will inhibit activation of TSHRs endogenously expressed in GOFs. Methods: Three strains of GOFs, previously obtained from patients with GO, were studied as undifferentiated fibroblasts (FIBs) and after differentiation into adipocytes (ADIPs), and another 7 strains were studied only as FIBs. ADIP differentiation was monitored by morphology and measurement of adiponectin mRNA. FIBs and ADIPs were treated with TSH or TSHR stimulating antibody M22 in the absence or presence of NCGC00229600 and TSHR activation was monitored by cAMP production. Results: FIBs contained few if any lipid vesicles and undetectable levels of adiponectin mRNA whereas ADIPs exhibited abundant lipid vesicles and levels of adiponectin mRNA more than 250,000 times greater than FIBs; TSHR mRNA levels were 10-fold higher in ADIPs than FIBs. FIBs exhibited higher absolute levels of basal and forskolin-stimulated cAMP production than ADIPs. Consistent with previous findings, TSH stimulated cAMP production in the majority of ADIP strains and less consistently in FIBs. Most importantly, NCGC00229600 reduced both TSH- and M22-stimulated cAMP production in GOFs. Conclusions: These data confirm previous findings that TSHR activation may cause increased cAMP production in GOFs and show that NCGC00229600 can inhibit TSHR activation in GOFs. These findings suggest that drug-like TSHR antagonists may have a role in treatment of GO.
  Thyroid: official journal of the American Thyroid Association 05/2012; · 2.60 Impact Factor