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Differential Signaling Profiles of MC4R Mutations with Three Different Ligands
Sarah Paisdzior1, Ioanna Maria Dimitriou1, Paul Curtis Schöpe2
1Institute 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.
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 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.
Insights
Melanocortin 4 receptor (MC4R) mutations, common in obesity, affect weight regulation. Different mutations cause varied signaling pathway changes, emphasizing the need for comprehensive analysis.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- The melanocortin 4 receptor (MC4R) is crucial for hypothalamic regulation of body weight and energy expenditure.
- MC4R mutations are the leading genetic cause of monogenic obesity, impacting its anorectic effects through Gs-dependent cyclic adenosine monophosphate (cAMP) signaling and other pathways.
Purpose of the Study:
- To investigate potential signaling bias among different MC4R mutations.
- To comprehensively characterize the signaling profiles of specific MC4R mutations across various pathways.
Main Methods:
- Investigated three major MC4R mutations: S127L (Gs loss-of-function), H158R (Gs gain-of-function), and V103I (common European SNP).
- Assessed signaling via all four major G protein families, extracellular regulated kinase (ERK) phosphorylation, and β-arrestin2 recruitment.
- Utilized endogenous agonists (α-MSH, β-MSH) and a synthetic agonist (NDP-α-MSH).
Main Results:
- The S127L mutation resulted in a complete loss-of-function across all tested pathways.
- The V103I and H158R mutations exhibited a bias towards the Gq/11 pathway when stimulated with endogenous ligands.
- Signaling pathway alterations varied significantly depending on the specific MC4R mutation.
Conclusions:
- MC4R mutations can differentially impact various signaling pathways, leading to diverse functional consequences.
- Comprehensive characterization of MC4R mutations across multiple signaling pathways is essential for understanding their role in obesity and for potential therapeutic strategies.
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