ArticleInternational journal of biological sciences2014
Defect in MAPK signaling as a cause for monogenic obesity caused by inactivating mutations in the melanocortin-4 receptor gene.
Article in International journal of biological sciences, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 56 citations in OpenAlex.
- Neural Melanocortin Receptors in Fish: Insights into Growth Regulation and Aquaculture Advancement.Biomolecules · 2026Review
- GPR45 modulates GαScience (New York, N.Y.) · 2025Article
- MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels.The Journal of clinical endocrinology and metabolism · 2024Article
- A Critical Functional Missense Mutation (T117M) in SheepAnimals : an open access journal from MDPI · 2024Article
- A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.The Journal of clinical investigation · 2024Article
- Protein Kinases in Obesity, and the Kinase-Targeted Therapy.Advances in experimental medicine and biology · 2024Review
- Functional Characterization of NovelInternational journal of molecular sciences · 2023Article
- Targeting the central melanocortin system for the treatment of metabolic disorders.Nature reviews. Endocrinology · 2023Review
- Divergent Pharmacology and Biased Signaling of the Four Melanocortin-4 Receptor Isoforms in Rainbow Trout (Biomolecules · 2023Article
- A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants.Journal of molecular endocrinology · 2023Article
- Melanocortin-5 Receptor: Pharmacology and Its Regulation of Energy Metabolism.International journal of molecular sciences · 2022Review
- Detecting genetic epistasis by differential departure from independence.Molecular genetics and genomics : MGG · 2022Article
- Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations.International journal of obesity (2005) · 2021 · on this mapArticle
- Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control.Frontiers in physiology · 2021Review
- Biased signaling in naturally occurring mutations of G protein-coupled receptors associated with diverse human diseases.Biochimica et biophysica acta. Molecular basis of disease · 2021Review
- Alanine Scanning Mutagenesis of the DRYxxI Motif and Intracellular Loop 2 of Human Melanocortin-4 Receptor.International journal of molecular sciences · 2020Article
- Structural Complexity and Plasticity of Signaling Regulation at the Melanocortin-4 Receptor.International journal of molecular sciences · 2020Review
- Differential Signaling Profiles of MC4R Mutations with Three Different Ligands.International journal of molecular sciences · 2020Article
- Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity.Frontiers in endocrinology · 2020Article
- Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective.Frontiers in endocrinology · 2019Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The melanocortin-4 receptor (MC4R) is a Family A G protein-coupled receptor that plays an essential role in regulating energy homeostasis, including both energy intake and expenditure. Mutations leading to a reduced MC4R function confer a major gene effect for obesity. More than 170 distinct mutations have been identified in humans. In addition to the conventional Gs-stimulated cAMP pathway, the MC4R also activates MAPKs, especially ERK1/2. We also showed there is biased signaling in the two signaling pathways, with inverse agonists in the Gs-cAMP pathway acting as agonists for the ERK1/2 pathway. In the current study, we sought to determine whether defects in basal or agonist-induced ERK1/2 activation in MC4R mutants might potentially contribute to obesity pathogenesis in patients carrying these mutations. The constitutive and ligand-stimulated ERK1/2 activation were measured in wild type and 73 naturally occurring MC4R mutations. We showed that nineteen mutants had significantly decreased basal pERK1/2 level, and five Class V variants (where no functional defects have been identified previously), C40R, V50M, T112M, A154D and S295P, had impaired ligand-stimulated ERK1/2 activation. Our studies demonstrated for the first time that decreased basal or ligand-stimulated ERK1/2 signaling might contribute to obesity pathogenesis caused by mutations in the MC4R gene. We also observed biased signaling in 25 naturally occurring mutations in the Gs-cAMP and ERK1/2 pathways.
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