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Open AccessArticle

Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

1
Institute of Experimental Pediatric Endocrinology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, D-10117 Berlin, Germany
2
Max Delbrück Center, Robert-Rössle-Straße 10, 13092 Berlin, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, D-97078 Würzburg, Germany
3
Group Protein X-ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Charité- Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, D-10117 Berlin, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(4), 1224; https://doi.org/10.3390/ijms21041224
Received: 19 December 2019 / Revised: 6 February 2020 / Accepted: 6 February 2020 / Published: 12 February 2020
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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. View Full-Text
Keywords: Melanocortin 4 receptor (MC4R); Melanocyte stimulating hormones MSH; G protein coupled receptor (GPCR); biased signaling Melanocortin 4 receptor (MC4R); Melanocyte stimulating hormones MSH; G protein coupled receptor (GPCR); biased signaling
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Paisdzior, S.; Dimitriou, I.M.; Schöpe, P.C.; Annibale, P.; Scheerer, P.; Krude, H.; Lohse, M.J.; Biebermann, H.; Kühnen, P. Differential Signaling Profiles of MC4R Mutations with Three Different Ligands. Int. J. Mol. Sci. 2020, 21, 1224.

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