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Differential signaling profiles of MC4R mutations with three different ligands
Please always quote using this URN: urn:nbn:de:bvb:20-opus-285108
- 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 investigatedThe 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.…
Author: | Sarah Paisdzior, Ioanna Maria Dimitriou, Paul Curtis Schöpe, Paolo Annibale, Patrick Scheerer, Heiko Krude, Martin J. Lohse, Heike Biebermann, Peter Kühnen |
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URN: | urn:nbn:de:bvb:20-opus-285108 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Institut für Pharmakologie und Toxikologie |
Language: | English |
Parent Title (English): | International Journal of Molecular Sciences |
ISSN: | 1422-0067 |
Year of Completion: | 2020 |
Volume: | 21 |
Issue: | 4 |
Article Number: | 1224 |
Source: | International Journal of Molecular Sciences (2020) 21:4, 1224. https://doi.org/10.3390/ijms21041224 |
DOI: | https://doi.org/10.3390/ijms21041224 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | G protein coupled receptor (GPCR); Melanocortin 4 receptor (MC4R); Melanocyte stimulating hormones MSH; biased signaling |
Release Date: | 2023/06/12 |
Date of first Publication: | 2020/02/12 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |