ArticleThe Journal of biological chemistry2009
Pertussis toxin-sensitive signaling of melanocortin-4 receptors in hypothalamic GT1-7 cells defines agouti-related protein as a biased agonist.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 105 citations in OpenAlex.
- MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.Nature medicine · 2018Trial
- 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
- MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor.Nature communications · 2025Article
- Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8.International journal of molecular sciences · 2024Article
- Automated Patch Clamp Recordings of GPCR-Gated Ion Channels: Targeting the MC4-R/Kir7.1 Potassium Channel Complex.Methods in molecular biology (Clifton, N.J.) · 2024Article
- A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants.Journal of molecular endocrinology · 2023Article
- The Mc4r gene is responsible for the development of experimentally induced testicular teratomas.Scientific reports · 2023Article
- The Complex Interplay between Imbalanced Mitochondrial Dynamics and Metabolic Disorders in Type 2 Diabetes.Cells · 2023Review
- The unique structural characteristics of the Kir 7.1 inward rectifier potassium channel: a novel player in energy homeostasis control.American journal of physiology. Cell physiology · 2023Review
- MC4R biased signalling and the conformational basis of biological function selections.Journal of cellular and molecular medicine · 2022Review
- Selective Signal Capture from Multidimensional GPCR Outputs with Biased Agonists: Progress Towards Novel Drug Development.Molecular diagnosis & therapy · 2022Review
- Molecular Analysis and Conformational Dynamics of Human MC4R Disease-Causing Mutations.Molecules (Basel, Switzerland) · 2022Article
- AgRP neurons: Regulators of feeding, energy expenditure, and behavior.The FEBS journal · 2022Review
- Discovery of Nanomolar Melanocortin-3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput "Unbiased" Screening Campaign.Journal of medicinal chemistry · 2021Article
- Evidence That Agouti-Related Peptide May Directly Regulate Kisspeptin Neurons in Male Sheep.Metabolites · 2021Article
- 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
- The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure.Frontiers in psychiatry · 2021Review
- Hypothalamic GPCR Signaling Pathways in Cardiometabolic Control.Frontiers in physiology · 2021Review
- Alanine Scanning Mutagenesis of the DRYxxI Motif and Intracellular Loop 2 of Human Melanocortin-4 Receptor.International journal of molecular sciences · 2020Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Melanocortin-4 receptor (MC4R)-induced anorexigenic signaling in the hypothalamus controls body weight and energy homeostasis. So far, MC4R-induced signaling has been exclusively attributed to its coupling to G(s) proteins. In line with this monogamous G protein coupling profile, most MC4R mutants isolated from obese individuals showed a reduced ability to activate G(s). However, some mutants displayed enhanced G(s) coupling, suggesting that signaling pathways independent of G(s) may be involved in MC4R-mediated anorexigenic signaling. Here we report that the G(s) signaling-deficient MC4R-D90N mutant activates G proteins in a pertussis toxin-sensitive manner, indicating that this mutant is able to selectively interact with G(i/o) proteins. Analyzing a hypothalamic cell line (GT1-7 cells), we observed activation of pertussis toxin-sensitive G proteins by the wild-type MC4R as well, reflecting multiple coupling of the MC4R to G(s) and G(i/o) proteins in an endogenous cell system. Surprisingly, the agouti-related protein, which has been classified as a MC4R antagonist, selectively activates G(i/o) signaling in GT1-7 cells. Thus, the agouti-related protein antagonizes melanocortin-dependent G(s) activation not only by competitive antagonism but additionally by initiating G(i/o) protein-induced signaling as a biased agonist.
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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.