Thyrotropin Receptor-Stimulating Graves' Disease Immunoglobulins Induce Hyaluronan Synthesis by Differentiated Orbital Fibroblasts from Patients with Graves' Ophthalmopathy Not Only Via Cyclic Adenosine Monophosphate Signaling Pathways

2011 ◽  
Vol 2011 ◽  
pp. 112-113
Author(s):  
M. Schott
Keyword(s):  
Signaling Pathways ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Graves Disease ◽  
Thyrotropin Receptor ◽  
Graves Ophthalmopathy ◽  
Orbital Fibroblasts

scholarly journals Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

2020 ◽  
Vol 21 (4) ◽  
pp. 1224 ◽  
Author(s):  
Sarah Paisdzior ◽  
Ioanna Maria Dimitriou ◽  
Paul Curtis Schöpe ◽  
Paolo Annibale ◽  
Patrick Scheerer ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Loss Of Function ◽  
Melanocyte Stimulating Hormone ◽  
Melanocortin 4 Receptor ◽  
Erk Phosphorylation ◽  
Extracellular Regulated Kinase ◽  
Peptide Agonist

The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin–melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.

Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil

Cephalalgia ◽  
2019 ◽  
Vol 39 (14) ◽  
pp. 1776-1788 ◽  
Author(s):  
Samaira Younis ◽  
Casper E Christensen ◽  
Nikolaj M Toft ◽  
Thomas Søborg ◽  
Faisal M Amin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Calcitonin Gene Related Peptide ◽  
Guanosine Monophosphate ◽  
Related Peptide ◽  
Intracellular Signaling Pathways ◽  
Calcitonin Gene

Objective Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. Methods Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. Results Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. Conclusion A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: ClinicalTrials.gov Identifier: NCT03143465.

scholarly journals 40 YEARS OF IGF1: IGF1 receptor and thyroid-associated ophthalmopathy

2018 ◽  
Vol 61 (1) ◽  
pp. T29-T43 ◽  
Author(s):  
Michelle Mohyi ◽  
Terry J Smith
Keyword(s):  
Graves Disease ◽  
Physical Interaction ◽  
Therapeutic Trial ◽  
Thyrotropin Receptor ◽  
Autoimmune Process ◽  
The Past ◽  
Thyroid Associated Ophthalmopathy ◽  
Upper Face ◽  
Igf1 Receptor ◽  
Orbital Fibroblasts

Thyroid-associated ophthalmopathy (TAO) is a vexing and poorly understood autoimmune process involving the upper face and tissues surrounding the eyes. In TAO, the orbit can become inflamed and undergo substantial remodeling that is disfiguring and can lead to loss of vision. There are currently no approved medical therapies for TAO, the consequence of its uncertain pathogenic nature. It usually presents as a component of the syndrome known as Graves’ disease where loss of immune tolerance to the thyrotropin receptor (TSHR) results in the generation of activating antibodies against that protein and hyperthyroidism. The role for TSHR and these antibodies in the development of TAO is considerably less well established. We have reported over the past 2 decades evidence that the insulin-like growth factorI receptor (IGF1R) may also participate in the pathogenesis of TAO. Activating antibodies against IGF1R have been detected in patients with GD. The actions of these antibodies initiate signaling in orbital fibroblasts from patients with the disease. Further, we have identified a functional and physical interaction between TSHR and IGF1R. Importantly, it appears that signaling initiated from either receptor can be attenuated by inhibiting the activity of IGF1R. These findings underpin the rationale for therapeutically targeting IGF1R in active TAO. A recently completed therapeutic trial of teprotumumab, a human IGF1R inhibiting antibody, in patients with moderate to severe, active TAO, indicates the potential effectiveness and safety of the drug. It is possible that other autoimmune diseases might also benefit from this treatment strategy.

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