ArticleThe Journal of biological chemistry2011
Mutually opposite signal modulation by hypothalamic heterodimerization of ghrelin and melanocortin-3 receptors.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 105 citations in OpenAlex.
- LEAP2 as a therapeutic target in obesity and cardiometabolic disorders.Reviews in endocrine & metabolic disorders · 2026Review
- A Dimer for Dinner: The Impact of GHS-R1a Heterodimerization on Feeding Circuits.Biomolecules · 2026Review
- Melanocortin 3 Receptors Do Not Specifically Localize to Primary Cilia in Cultured Human and Rodent Neurons.Cell biochemistry and function · 2026Article
- Effect of a partial loss of function MC3R mutation on MC3R+GHSR-1A heterodimer activity and RNF11 regulation.Journal of endocrinological investigation · 2026Article
- Ghrelin Increases Glutamate Release at the Perforant Path-Dentate Gyrus Granule Cell Synapses by Cross-Activating Dopamine DJournal of cellular physiology · 2025Article
- Pro-Opiomelanocortin and Melanocortin Receptor 3 and 4 Mutations in Genetic Obesity.Biomolecules · 2025Review
- An Emerging Role for Gut-Brain Signaling Involving Ghrelin in Chronic Stress.Advances in experimental medicine and biology · 2025Review
- The effects of ghrelin and LEAP-2 in energy homeostasis are modulated by thermoneutrality, high-fat diet and aging.Journal of endocrinological investigation · 2024Article
- Melanocortin-4 Receptor PLC Activation Is Modulated by an Interaction with the Monocarboxylate Transporter 8.International journal of molecular sciences · 2024Article
- Regulation of the length of neuronal primary cilia and its potential effects on signalling.Trends in cell biology · 2023Review
- Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics.Molecules (Basel, Switzerland) · 2023Review
- Cloning, distribution, and effects of growth regulation of MC3R and MC4R in red crucian carp (Frontiers in endocrinology · 2023Article
- "Sibling" battle or harmony: crosstalk between nesfatin-1 and ghrelin.Cellular and molecular life sciences : CMLS · 2022Review
- The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: potential relevance for brain and behavior.Frontiers in molecular neuroscience · 2022Review
- The emerging role of heterodimerisation and interacting proteins in ghrelin receptor function.The Journal of endocrinology · 2021Review
- GHS-R suppression in adipose tissues protects against obesity and insulin resistance by regulating adipose angiogenesis and fibrosis.International journal of obesity (2005) · 2021Article
- Role of the Endocannabinoid System in the Adipose Tissue with Focus on Energy Metabolism.Cells · 2021Review
- "A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes".Molecular metabolism · 2021Review
- Metabolic insights from a GHSR-A203E mutant mouse model.Molecular metabolism · 2020Article
- Integration of Cell-Free Expression and Solid-State NMR to Investigate the Dynamic Properties of Different Sites of the Growth Hormone Secretagogue Receptor.Frontiers in pharmacology · 2020Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Interaction and cross-talk of G-protein-coupled receptors (GPCRs) are of considerable interest because an increasing number of examples implicate a profound functional and physiological relevance of homo- or hetero-oligomeric GPCRs. The ghrelin (growth hormone secretagogue receptor (GHSR)) and melanocortin-3 (MC3R) receptors are both known to have orexigenic effects on the hypothalamic control of body weight. Because in vitro studies indicate heterodimerization of GHSR and MC3R, we investigated their functional interplay. Combined in situ hybridization and immunohistochemistry indicated that the vast majority of GHSR-expressing neurons in the arcuate nucleus also express MC3R. In vitro coexpression of MC3R and GHSR promoted enhanced melanocortin-induced intracellular cAMP accumulation compared with activation of MC3R in the absence of GHSR. In contrast, agonist-independent basal signaling activity and ghrelin-induced signaling of GHSR were impaired, most likely due to interaction with MC3R. By taking advantage of naturally occurring GHSR mutations and an inverse agonist for GHSR, we demonstrate that the observed enhanced MC3R signaling capability depends directly on the basal activity of GHSR. In conclusion, we demonstrate a paradigm-shifting example of GPCR heterodimerization allowing for mutually opposite functional influence of two hypothalamic receptors controlling body weight. We found that the agonist-independent active conformation of one GPCR can determine the signaling modalities of another receptor in a heterodimer. Our discovery also implies that mutations within one of two interacting receptors might affect both receptors and different pathways simultaneously. These findings uncover mechanisms of important relevance for pharmacological targeting of GPCR in general and hypothalamic body weight regulation in particular.
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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.