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| Item Type: | Article |
|---|---|
| Title: | Differential signaling profiles of MC4R mutations with three different ligands |
| Creators Name: | Paisdzior, S. and Dimitriou, I.M. and Schöpe, P.C. and Annibale, P. and Scheerer, P. and Krude, H. and Lohse, M.J. and Biebermann, H. and Kühnen, P. |
| 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 G(S)-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 G(S) loss-of-function (S127L) and a G(S) 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 G(q/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. |
| Keywords: | Melanocortin 4 Receptor (MC4R), Melanocyte Stimulating Hormones MSH, G Protein Coupled Receptor (GPCR), Biased Signaling |
| Source: | International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| Publisher: | MDPI |
| Volume: | 21 |
| Number: | 4 |
| Page Range: | 1224 |
| Date: | 12 February 2020 |
| Official Publication: | https://doi.org/10.3390/ijms21041224 |
| PubMed: | View item in PubMed |
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