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Differential signaling profiles of MC4R mutations with three different ligands

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Item Type:Article
Title:Differential signaling profiles of MC4R mutations with three different ligands
Creators Name:Paisdzior, S., Dimitriou, I.M., Schöpe, P.C., Annibale, P., Scheerer, P., Krude, H., Lohse, M.J., 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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