Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

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 cha...

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Main Authors:	Sarah Paisdzior, Ioanna Maria Dimitriou, Paul Curtis Schöpe, Paolo Annibale, Patrick Scheerer, Heiko Krude, Martin J. Lohse, Heike Biebermann, Peter Kühnen
Format:	Article
Language:	English
Published:	MDPI AG 2020-02-01
Series:	International Journal of Molecular Sciences
Subjects:	melanocortin 4 receptor (mc4r) melanocyte stimulating hormones msh g protein coupled receptor (gpcr) biased signaling
Online Access:	https://www.mdpi.com/1422-0067/21/4/1224

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record_format	Article
spelling	doaj-4bd0a93b3bf74807b3fc322af89433462020-11-25T01:38:25ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-02-01214122410.3390/ijms21041224ijms21041224Differential Signaling Profiles of MC4R Mutations with Three Different LigandsSarah Paisdzior0Ioanna Maria Dimitriou1Paul Curtis Schöpe2Paolo Annibale3Patrick Scheerer4Heiko Krude5Martin J. Lohse6Heike Biebermann7Peter Kühnen8Institute 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, GermanyInstitute 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, GermanyMax Delbrück Center, Robert-Rössle-Straße 10, 13092 Berlin, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, D-97078 Würzburg, GermanyMax Delbrück Center, Robert-Rössle-Straße 10, 13092 Berlin, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, D-97078 Würzburg, GermanyGroup 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, GermanyInstitute 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, GermanyMax Delbrück Center, Robert-Rössle-Straße 10, 13092 Berlin, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, D-97078 Würzburg, GermanyInstitute 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, GermanyInstitute 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, GermanyThe 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 between the different signaling pathways, we investigated three major <i>MC4R</i> mutations: a G<sub>S</sub> loss-of-function (S127L) and a G<sub>S</sub> 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<sub>q/11</sub> pathway when challenged with the endogenous ligands. These results show that <i>MC4R</i> mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.https://www.mdpi.com/1422-0067/21/4/1224melanocortin 4 receptor (mc4r)melanocyte stimulating hormones mshg protein coupled receptor (gpcr)biased signaling
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Sarah Paisdzior Ioanna Maria Dimitriou Paul Curtis Schöpe Paolo Annibale Patrick Scheerer Heiko Krude Martin J. Lohse Heike Biebermann Peter Kühnen
spellingShingle	Sarah Paisdzior Ioanna Maria Dimitriou Paul Curtis Schöpe Paolo Annibale Patrick Scheerer Heiko Krude Martin J. Lohse Heike Biebermann Peter Kühnen Differential Signaling Profiles of MC4R Mutations with Three Different Ligands International Journal of Molecular Sciences melanocortin 4 receptor (mc4r) melanocyte stimulating hormones msh g protein coupled receptor (gpcr) biased signaling
author_facet	Sarah Paisdzior Ioanna Maria Dimitriou Paul Curtis Schöpe Paolo Annibale Patrick Scheerer Heiko Krude Martin J. Lohse Heike Biebermann Peter Kühnen
author_sort	Sarah Paisdzior
title	Differential Signaling Profiles of MC4R Mutations with Three Different Ligands
title_short	Differential Signaling Profiles of MC4R Mutations with Three Different Ligands
title_full	Differential Signaling Profiles of MC4R Mutations with Three Different Ligands
title_fullStr	Differential Signaling Profiles of MC4R Mutations with Three Different Ligands
title_full_unstemmed	Differential Signaling Profiles of MC4R Mutations with Three Different Ligands
title_sort	differential signaling profiles of mc4r mutations with three different ligands
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1422-0067
publishDate	2020-02-01
description	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 between the different signaling pathways, we investigated three major <i>MC4R</i> mutations: a G<sub>S</sub> loss-of-function (S127L) and a G<sub>S</sub> 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<sub>q/11</sub> pathway when challenged with the endogenous ligands. These results show that <i>MC4R</i> mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.
topic	melanocortin 4 receptor (mc4r) melanocyte stimulating hormones msh g protein coupled receptor (gpcr) biased signaling
url	https://www.mdpi.com/1422-0067/21/4/1224
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Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

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