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Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.

ABSTRACT: 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.

SUBMITTER: Paisdzior S

PROVIDER: S-EPMC7072973 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.

Paisdzior Sarah S Dimitriou Ioanna Maria IM Schöpe Paul Curtis PC Annibale Paolo P Scheerer Patrick P Krude Heiko H Lohse Martin J MJ Biebermann Heike H Kühnen Peter P

International journal of molecular sciences 20200212 4

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 G<sub>S</sub>-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations bet ...[more]

PMID: 32059383

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Project description:BackgroundJohne's disease is a chronic inflammatory disease of the gut caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP). Symptoms include wasting, diarrhoea, loss of condition and eventual death. Three forms of Johne's disease have been described in sheep - paucibacillary, multibacillary and asymptomatic. The paucibacillary form is characterized by an inflammatory, Th1-type immune response. The multibacillary form of the disease, which disseminates the infection, is characterized by macrophage infiltration mediated by a Th2-type immune response, and asymptomatic animals have no clinical symptoms or pathology but are infected with MAP. What determines these three forms of the disease is unknown. To further understand these differences, we used real-time RT-PCR to compare the expression of thirteen cytokine and cytokine-related genes in ileal tissue from sheep with the three forms of the disease.ResultsThree pathological forms of sheep paratuberculosis were defined on the basis of histopathology, cytochemistry (Zeihl-Neelsen) and IS900 PCR. Paucibacillary lesions have largely T cell and eosinophil infiltration and are ZN negative; multibacillary lesions have macrophage infiltration and large numbers of acid-fast bacteria. The pauci- and multibacillary forms are linked to the differential expression of IFN gamma and IL-10 respectively. In addition the increased levels of the proinflammatory cytokines (IL-1 beta and TNFalpha), IL-8, IL-18 and TRAF-1 in both diseased forms is indicative of persistent inflammatory lesions. No changes were seen in IL-1 alpha in any sheep ileum tissues. Asymptomatic animals are IS900+ with normal histology but have significantly decreased levels of IL-18 and increased levels TNFalpha.ConclusionWe have quantified the expression levels of thirteen cytokine and cytokine related genes in three forms of ovine paratuberculosis using real-time PCR analyses and confirm that sheep pauci- and multibacillary disease are linked to type 1 and type 2 T cell responses respectively. The expression patterns of other cytokines shows that both disease forms have an inflammatory aetiology but that the central role for IL-1 alpha in bovine paratuberculosis is not seen in the sheep infection. Asymptomatic animals are infected and show no pathology but can be distinguished, in terms of cytokine expression pattern, from uninfected controls.

Dataset Information

Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.

Publications

Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.

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