ArticleNature2015
G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers.
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Who cites it
113 citing papers in PubMed, 192 citations in OpenAlex.
- MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.Nature medicine · 2018Trial
- Functional coupling between MC4R and Kir7.1 contributes to clozapine-induced weight gain in female mice.Nature communications · 2026Article
- Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders.Acta pharmaceutica Sinica. B · 2026Review
- Structural and functional studies of inward rectifier Kir7.1 and its regulation by the Melanocortin-4 receptor.Nature communications · 2026Article
- Neural Melanocortin Receptors in Fish: Insights into Growth Regulation and Aquaculture Advancement.Biomolecules · 2026Review
- The role of accessory proteins and co-factors in regulation of melanocortin-4 receptor signalling: An update.Journal of neuroendocrinology · 2026Review
- POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons.eLife · 2025Article
- GPR45 modulates GαScience (New York, N.Y.) · 2025Article
- Dopaminergic neurons in the paraventricular hypothalamus extend the food consumption phase.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Inwardly rectifying potassium channels regulate membrane potential polarization and direction sensing during neutrophil chemotaxis.bioRxiv : the preprint server for biology · 2025Article
- Hypothalamic opsin 3 suppresses MC4R signaling and potentiates Kir7.1 to promote food consumption.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Carbocyclic setmelanotide analogs maintain biochemical potency at melanocortin 4 receptors.Journal of peptide science : an official publication of the European Peptide Society · 2025Article
- Article
- Melanocortin 4 receptor mutation in obesity.World journal of experimental medicine · 2024Review
- Characterization of four structurally diverse inhibitors of SUR2-containing KChannels (Austin, Tex.) · 2024Article
- A biological rhythm in the hypothalamic system links sleep-wake cycles with feeding-fasting cycles.Scientific reports · 2024Article
- Structure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist.Nature communications · 2024Article
- Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity.Current obesity reports · 2024Review
- Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States.bioRxiv : the preprint server for biology · 2024Article
- A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.The Journal of clinical investigation · 2024Article
53 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.