A Drug-like Antagonist Inhibits TSH Receptor-Mediated Stimulation of cAMP Production in Graves’ Orbital Fibroblasts

Thyroid ◽  
2012 ◽  
pp. 120517084830005 ◽  
Author(s):  
Marvin C Gershengorn ◽  
Susanne Neumann ◽  
Arthur Pope ◽  
Elizabeth Geras-Raaka ◽  
Bruce M Raaka ◽  
...  
Keyword(s):  
Tsh Receptor ◽  
Camp Production ◽  
Orbital Fibroblasts ◽  
Stimulation Of

scholarly journals Experimental Reproduction of Dynamic Fluctuation of TSH Receptor–Binding Antibodies Between Stimulation and Inhibition

2019 ◽  
Vol 3 (12) ◽  
pp. 2361-2373
Author(s):  
Tetsuya Tagami ◽  
Kaho Hiroshima-Hamanaka ◽  
Hironobu Umakoshi ◽  
Mika Tsuiki-Naruse ◽  
Toru Kusakabe ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Tsh Receptor ◽  
Graves Disease ◽  
Camp Production ◽  
Isolated Cells ◽  
Human Mabs ◽  
Experimental Reproduction ◽  
Dynamic Fluctuation ◽  
Stimulation Of

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.

scholarly journals A Drug-Like Antagonist Inhibits Thyrotropin Receptor–Mediated Stimulation of cAMP Production in Graves' Orbital Fibroblasts

Thyroid ◽  
2012 ◽  
Vol 22 (8) ◽  
pp. 839-843 ◽  
Author(s):  
Susanne Neumann ◽  
Arthur Pope ◽  
Elizabeth Geras-Raaka ◽  
Bruce M. Raaka ◽  
Rebecca S. Bahn ◽  
...  
Keyword(s):  
Thyrotropin Receptor ◽  
Camp Production ◽  
Orbital Fibroblasts ◽  
Stimulation Of

Prostaglandin E2-histamine in interactions on cAMP, cGMP, and acid production in isolated fundic glands

1982 ◽  
Vol 242 (1) ◽  
pp. G21-G26 ◽  
Author(s):  
R. A. Levine ◽  
K. R. Kohen ◽  
E. H. Schwartzel ◽  
C. E. Ramsay
Keyword(s):  
Prostaglandin E2 ◽  
Acid Secretion ◽  
Acid Production ◽  
Camp Production ◽  
Histamine Stimulation ◽  
Fundic Mucosa ◽  
Biochemical Responses ◽  
Camp Levels ◽  
Camp And Cgmp ◽  
Stimulation Of

Relations among cAMP, cGMP, acid production [measured by the intraglandular accumulation of [14C]aminopyrine (AP)], and prostaglandin E2 (PGE2) activity were studied in isolated glands from rabbit fundic mucosa. AP, cAMP, and cGMP responses to histamine, PGE2, and 3-isobutyl-1-methylxanthine (IMX) were compared with controls. Histamine and PGE2 significantly increased glandular cAMP levels twofold, and histamine and IMX stimulated AP uptake two- to fourfold. PGE2 significantly inhibited both histamine- and IMX-stimulated AP accumulation, but it did not alter basal AP uptake. PGE2 also decreased histamine-stimulated cAMP production but only at a low concentration (10(-7) M). This dose of PGE2 was near to the endogenous PGE2 content found in unstimulated glands (10(-8) M). Intraglandular cGMP levels in unstimulated glands (10(-8) M). Intraglandular cGMP levels were increased by IMX but not by PGE2 or histamine. It is concluded that histamine stimulation of acid secretion is mediated by cAMP, that secretory and biochemical responses to histamine are modulated by PGE2 because PGE2 antagonized histamine-stimulated cAMP and AP uptake, and that the rise in cAMP induced solely by PGE2 appears to be localized within nonparietal cells because PGE2 alone did not stimulate AP accumulation.

scholarly journals A Selective TSH Receptor Antagonist Inhibits Stimulation of Thyroid Function in Female Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 310-314 ◽  
Author(s):  
Susanne Neumann ◽  
Eshel A. Nir ◽  
Elena Eliseeva ◽  
Wenwei Huang ◽  
Juan Marugan ◽  
...  
Keyword(s):  
Small Molecule ◽  
Sodium Iodide ◽  
Cell System ◽  
Tsh Receptor ◽  
Free T4 ◽  
Serum Free ◽  
Stimulation Of ◽  
Lowered Serum

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.

MATURATIONAL CHANGES IN SHEEP OVARIAN FOLLICLES: GONADOTROPHIC STIMULATION OF CYCLIC AMP PRODUCTION BY ISOLATED THECA AND GRANULOSA CELLS

1978 ◽  
Vol 89 (1) ◽  
pp. 166-172 ◽  
Author(s):  
T. J. Weiss ◽  
D. T. Armstrong ◽  
J. E. A. McIntosh ◽  
R. F. Seamark
Keyword(s):  
Cyclic Amp ◽  
Granulosa Cells ◽  
Follicle Stimulating Hormone ◽  
Adenosine Monophosphate ◽  
Ovarian Follicles ◽  
Chorionic Gonadotrophin ◽  
Human Chorionic Gonadotrophin ◽  
Camp Production ◽  
Stimulation Of ◽  
Stimulating Hormone

ABSTRACT Theca and granulosa tissues isolated from sheep ovarian follicles of different sizes were incubated in the presence of human chorionic gonadotrophin (HCG; 5 IU/ml) or follicle stimulating hormone (FSH; 5 μg NIH-FSH-S11/ml) for 40 min. Changes in the total amounts of cyclic 3′,5′-adenosine monophosphate (cAMP) were used as an index of the responsiveness of these preparations to the hormones. Thecal tissue of both large (4–6 mm in diameter) and small (1–3 mm) follicles responded similarly to gonadotrophins. Granulosa cells from small follicles failed to respond to stimulation by HCG. FSH, however, consistently increased cAMP production in comparison with controls or cells treated with HCG. Granulosa cells of large follicles responded to both HCG and FSH.

Stimulation of thyroid-stimulating hormone (TSH) receptor antibody production following painless thyroiditis

2004 ◽  
Vol 60 (1) ◽  
pp. 49-53 ◽  
Author(s):  
Makoto Iitaka ◽  
Nils G. Morgenthaler ◽  
Naoko Momotani ◽  
Atsuo Nagata ◽  
Naofumi Ishikawa ◽  
...  
Keyword(s):  
Antibody Production ◽  
Thyroid Stimulating Hormone ◽  
Tsh Receptor ◽  
Receptor Antibody ◽  
Tsh Receptor Antibody ◽  
Painless Thyroiditis ◽  
Stimulation Of ◽  
Stimulating Hormone

Insulin-like growth factor-1 enhances the expression of functional TSH receptor in orbital fibroblasts from thyroid-associated ophthalmopathy

Immunobiology ◽  
2020 ◽  
Vol 225 (2) ◽  
pp. 151902
Author(s):  
Ji Sun Paik ◽  
Sung-Eun Kim ◽  
Ji Hyun Kim ◽  
Ji-Young Lee ◽  
Suk-Woo Yang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tsh Receptor ◽  
Insulin Like Growth Factor ◽  
Thyroid Associated Ophthalmopathy ◽  
Orbital Fibroblasts

Selected Contribution: Long-term effects of β2-adrenergic receptor stimulation on alveolar fluid clearance in mice

2002 ◽  
Vol 93 (5) ◽  
pp. 1875-1880 ◽  
Author(s):  
C. Sartori ◽  
X. Fang ◽  
D. W. McGraw ◽  
P. Koch ◽  
M. E. Snider ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Fluid Transport ◽  
Alveolar Fluid Clearance ◽  
Camp Production ◽  
Long Term Effects ◽  
Agonist Stimulation ◽  
Β2 Adrenergic Receptor ◽  
Stimulation Of ◽  
Alveolar Edema

Stimulation of active fluid transport with β-adrenergic receptor (βAR) agonists can accelerate the resolution of alveolar edema. However, chronic βAR-agonist administration may cause βAR desensitization and downregulation that may impair physiological responsiveness to βAR-agonist stimulation. Therefore, we measured baseline and terbutaline- (10−3 M) stimulated alveolar fluid clearance in mice that received subcutaneously (miniosmotic pumps) either saline or albuterol (2 mg · kg−1 · day−1) for 1, 3, or 6 days. Continuous albuterol administration increased plasma albuterol levels (10−5 M), an effect that was associated with 1) a significant decrease in βAR density and 2) attenuation, but not ablation, of maximal terbutaline-induced cAMP production. Forskolin-mediated cAMP-release was unaffected. Continuous albuterol infusion stimulated alveolar fluid clearance on day 1 but did not increase alveolar fluid clearance on days 3 and 6. However, terbutaline-stimulated alveolar fluid clearance in albuterol-treated mice was not reduced compared with saline-treated mice. Despite significant reductions in βAR density and agonist-mediated cAMP production by long-term βAR-agonist exposure, maximal βAR-agonist-mediated increase in alveolar fluid clearance is not diminished in mice.

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