Affinage

MC3R

Melanocortin receptor 3 · UniProt P41968

Length
323 aa
Mass
36.0 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC3R is a melanocortin G-protein-coupled receptor that couples energy status to the central regulation of feeding, growth, puberty, locomotion, and anxiety, and that mediates peripheral anti-inflammatory signaling (PMID:34732894, PMID:30541071). The receptor is activated by melanocortin peptides through their conserved His-Phe-Arg-Trp core, in which Met4, Phe7, Arg8, and Trp9 are critical for binding affinity, while subtype-selective recognition is governed by transmembrane domains TM1–TM3 and TM7 and specific residues such as position 157 in TM3 (PMID:8062918, PMID:9658201, PMID:12604699). Distinct from the closely related MC4R, MC3R couples to both Gs (cAMP) and Gq (inositol phosphate) signaling, a difference dictated by its third intracellular loop (PMID:11168397, PMID:12045190). AgRP serves as both an antagonist of melanocortin-stimulated signaling and an inverse agonist of MC3R constitutive activity, and the accessory protein MRAP2 physically associates with the receptor to shift its pharmacology toward enhanced ACTH sensitivity (PMID:9299416, PMID:28512117). Centrally, MC3R is the predominant melanocortin receptor on arcuate NPY neurons and acts as an inhibitory autoreceptor regulating orexigenic AgRP/NPY tone, food anticipatory activity, and energy-sensitive timing of sexual maturation and linear growth (PMID:16508337, PMID:16274853, PMID:25211592, PMID:34732894, PMID:37339320). MC3R-expressing neurons form defined circuits, including lateral hypothalamic neurons controlling locomotion and energy expenditure and paraventricular thalamic neurons that receive direct AgRP/POMC innervation and link energy state to anxiety behavior (PMID:30541071, PMID:37591737). In the periphery, macrophage- and epithelium-expressed MC3R mediates protection against myocardial and lung ischemia/inflammatory injury by suppressing cytokine release and NFκB signaling (PMID:15277567, PMID:18992358, PMID:22837805). Loss-of-function MC3R variants in humans cause delayed puberty, reduced linear growth, and increased adiposity (PMID:26818770, PMID:34732894, PMID:37339320).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1994 High

    Established the molecular determinants of ligand recognition by defining the receptor's glycosylated structure and which melanocortin core residues drive binding affinity.

    Evidence Photoaffinity labeling and alanine-scanning of alpha-MSH against rat MC3R membranes

    PMID:8062918

    Open questions at the time
    • No high-resolution structure of the ligand-bound receptor
    • Did not address subtype-selective contacts
  2. 1996 Medium

    Resolved an ambiguity in receptor architecture by showing the proposed long N-terminus is dispensable for ligand binding.

    Evidence Mutagenesis of alternative initiation codons and binding assay in COS cells

    PMID:8957262

    Open questions at the time
    • Single study
    • No functional signaling consequences explored
  3. 1997 High

    Defined AgRP as an endogenous antagonist at MC3R, identifying a negative regulator of melanocortin signaling relevant to energy balance.

    Evidence Radioligand competition and cAMP assays with recombinant human MC3R/MC4R/MC5R in COS-7 cells

    PMID:9299416

    Open questions at the time
    • Inverse-agonist activity on constitutive signaling not yet shown
    • In vivo relevance not addressed in this study
  4. 1998 Medium

    Mapped the transmembrane regions conferring subtype-specific peptide binding, distinguishing MC3R recognition from related melanocortin receptors.

    Evidence Chimeric MC1/MC3 receptor domain swapping with radioligand binding

    PMID:9658201

    Open questions at the time
    • Domain-level resolution only
    • Did not test signaling selectivity
  5. 1999 High

    Identified ligand and receptor residues governing MC3R vs MC4R selectivity, explaining how peptide conformation tunes subtype preference.

    Evidence Reciprocal chimeric MC3R/MC4R and MC4R Tyr268 mutagenesis with cAMP assays

    PMID:10358030

    Open questions at the time
    • Mechanism inferred as conformational rather than direct contact
    • No structural confirmation
  6. 2001 Medium

    Distinguished MC3R from MC4R signaling by showing MC3R engages both Gs and Gq pathways, broadening its downstream effector repertoire.

    Evidence CRE-luciferase and inositol phosphate assays in HEK293T cells

    PMID:11168397

    Open questions at the time
    • Heterologous system only
    • Physiological role of Gq coupling not established
  7. 2002 High

    Localized the structural basis of MC3R's differential G-protein coupling to its third intracellular loop, identifying the residues responsible.

    Evidence Chimeric and point-mutant MC3R/MC4R analysis with cAMP and IP readouts in HEK293T cells

    PMID:12045190

    Open questions at the time
    • Native cell coupling not tested
    • No structural model of receptor-G protein interface
  8. 2002 Medium

    Provided first in vivo evidence that MC3R mediates melanocortin cardioprotection against ischemia/reperfusion arrhythmias independent of MC4R and adrenal output.

    Evidence Rat ischemia/reperfusion model with selective agonist/antagonist dissection and adrenalectomy controls

    PMID:12122505

    Open questions at the time
    • Pharmacological dissection without genetic confirmation
    • Cellular site of action not yet defined
  9. 2003 Medium

    Pinpointed TM3 position 157 as a determinant of MC3R ligand selectivity, refining the structural map of subtype discrimination.

    Evidence Reciprocal MC3R/MC4R site-directed mutagenesis with binding and cAMP assays

    PMID:12604699

    Open questions at the time
    • Effect inferred to be indirect via Asp122 orientation
    • Single lab
  10. 2004 Medium

    Identified heart macrophages as the cellular site of MC3R-mediated cardioprotection, linking receptor anti-inflammatory action to a defined immune cell type.

    Evidence Immunogold localization plus mouse ischemia/reperfusion with pharmacological dissection and MC1R-mutant controls

    PMID:15277567

    Open questions at the time
    • No MC3R-null confirmation in this study
    • Downstream macrophage signaling not detailed
  11. 2005 Medium

    Demonstrated that MC3R-selective agonism increases feeding, supporting an inhibitory autoreceptor role on POMC neurons.

    Evidence Peripheral injection of D-Trp8-gamma-MSH in mice with food intake measurement

    PMID:16274853

    Open questions at the time
    • Receptor specificity inferred pharmacologically
    • Site of action not directly mapped
  12. 2005 Medium

    Linked human MC3R variants to obesity by showing the Thr6Lys+Val81Ile double mutant partially inactivates receptor binding, signaling, and expression.

    Evidence In vitro binding, cAMP, and protein expression of WT vs double-mutant MC3R

    PMID:16123355

    Open questions at the time
    • In vitro only
    • Causal mechanism in humans not established here
  13. 2006 Medium

    Established MC3R as the predominant melanocortin receptor on arcuate NPY neurons, defining the anatomical substrate for direct melanocortin modulation of orexigenic neurons.

    Evidence Double in situ hybridization in rat arcuate nucleus

    PMID:16508337

    Open questions at the time
    • Co-localization only
    • Functional consequence on NPY neuron activity not directly tested
  14. 2008 High

    Used genetic knockout to confirm MC3R as the receptor mediating melanocortin anti-inflammatory effects on alveolar macrophages in lung inflammation.

    Evidence Western blot, cAMP assays, and allergic/LPS lung inflammation models in WT, MC1R-mutant, and MC3R-null mice

    PMID:18992358

    Open questions at the time
    • Downstream anti-inflammatory signaling cascade not fully resolved
  15. 2009 Medium

    Dissected MC3R from MC4R function in metabolism, showing MC4R drives anorectic weight loss while MC3R may contribute to glucose homeostasis.

    Evidence Melanocortin agonist treatment of MC3R-KO, MC4R-KO, and WT mice with metabolic readouts

    PMID:19646498

    Open questions at the time
    • MC3R-specific glucose role inferred rather than directly proven
    • Single lab
  16. 2012 Medium

    Extended MC3R anti-inflammatory function to airway epithelium, showing receptor activation suppresses NFκB-driven inflammatory output.

    Evidence NFκB reporter, chemokine ELISA, and antagonist assays in human bronchial epithelial cells with in vivo localization

    PMID:22837805

    Open questions at the time
    • Immortalized cell line
    • In vivo epithelial role not genetically confirmed
  17. 2013 Medium

    Revealed an antagonistic interaction between MC3R and MC4R in ethanol-related behavior, showing MC3R deletion enhances MC4R-mediated effects.

    Evidence ICV MTII in MC3R-KO vs WT mice using binge ethanol protocol

    PMID:24290566

    Open questions at the time
    • Circuit and cellular basis not defined
    • Single behavioral paradigm
  18. 2014 Medium

    Showed MC3R is required for food anticipatory activity, mechanistically linking it to pre-meal AgRP/NPY regulation.

    Evidence Restricted-feeding behavior in MC3R-KO, GHSR-KO, and double-KO mice with hypothalamic AgRP/Npy mRNA measurement

    PMID:25211592

    Open questions at the time
    • Correlative mRNA link
    • Causal circuit not directly manipulated
  19. 2016 High

    Demonstrated causality of human MC3R variants in body composition using humanized knock-in mice, implicating MC3R in nutrient partitioning and adipose development.

    Evidence Homozygous hWT vs hDM MC3R knock-in mice with body composition, adiponectin, and adipocyte differentiation assays plus human data

    PMID:26818770

    Open questions at the time
    • Cell-autonomous vs central contributions not fully separated
  20. 2017 Medium

    Identified MRAP2 as a physical partner that modulates MC3R pharmacology and ACTH sensitivity, and confirmed AgRP as an inverse agonist of constitutive activity.

    Evidence Co-immunoprecipitation and CRE-luciferase reporter assays in CHO cells (chicken ortholog)

    PMID:28512117

    Open questions at the time
    • Ortholog study in heterologous cells
    • Human MC3R-MRAP2 stoichiometry not defined
  21. 2019 High

    Defined lateral hypothalamic MC3R neurons as a circuit controlling locomotion and energy expenditure independent of food intake.

    Evidence Cre-dependent tracing, chemogenetic activation, and ablation in Mc3rcre mice with calorimetry and body composition

    PMID:30541071

    Open questions at the time
    • Downstream effector targets of these neurons not fully mapped
  22. 2021 High

    Established MC3R as an energy-sensitive regulator of pubertal timing and linear growth through convergent human genetics and mouse knockout.

    Evidence Human MC3R loss-of-function study and Mc3r-null mouse phenotyping with hypothalamic expression analysis

    PMID:34732894

    Open questions at the time
    • Precise neuroendocrine relay to GnRH/growth axes not fully defined
  23. 2023 Medium

    Reinforced MC3R's role in pubertal tempo by showing loss-of-function variants are enriched in constitutional delay of growth and puberty.

    Evidence MC3R sequencing and variant functional characterization in CDGP and nIHH cohorts vs controls

    PMID:37339320

    Open questions at the time
    • Single cohort association
    • Mechanism specific to CDGP vs nIHH not resolved
  24. 2023 High

    Identified a paraventricular thalamic MC3R circuit linking energy status to anxiety behavior via direct AgRP/POMC innervation.

    Evidence Tract tracing, calcium imaging, and bidirectional chemogenetics with behavioral assays in Mc3rcre mice

    PMID:37591737

    Open questions at the time
    • Downstream targets of PVT MC3R neurons not mapped
    • Receptor signaling within these neurons not directly probed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MC3R's dual Gs/Gq signaling, MRAP2 modulation, and distinct neuronal circuits are integrated to control growth, puberty, anxiety, and peripheral inflammation in vivo remains unresolved.
  • No high-resolution structure of human MC3R
  • Native cell-type-specific G-protein coupling not defined
  • Mechanistic link between receptor signaling and downstream neuroendocrine axes incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
AGRPMRAP2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Agouti-related protein (ART/AgRP) functions as an antagonist at human MC3R and MC4R, inhibiting binding of radiolabeled alpha-MSH analog and blocking receptor-mediated cAMP signaling, with approximately 100-fold greater potency than agouti at MC3R/MC4R; it shows no potent antagonism at MC5R. Radioligand binding competition assay and functional cAMP assay in COS-7 cells expressing recombinant human MC3R, MC4R, and MC5R Biochemical and biophysical research communications High 9299416
1994 Photoaffinity labeling of rat MC3R expressed in membrane preparations identified the native receptor at 53–56 kDa (35 kDa after deglycosylation with PNGase F), consistent with N-linked glycosylation. Alanine-scanning mutagenesis of alpha-MSH showed that residues Met4, Phe7, Arg8, and Trp9 within the conserved core sequence His-Phe-Arg-Trp are critical for ligand binding affinity at MC3R. Photoaffinity labeling with radiolabeled photoreactive alpha-MSH analog followed by SDS-PAGE/autoradiography; radioligand binding assays with alanine-substituted alpha-MSH analogs FEBS letters High 8062918
1996 Mutagenesis of two alternative translation initiation codons (the originally proposed site and an alternate site 111 bp downstream) and deletion of the intervening sequence showed that both sites can serve as sole initiation sites and that the proposed long N-terminus of human MC3R is not required for ligand binding. Site-directed mutagenesis, expression in COS cells, radioligand binding assay European journal of pharmacology Medium 8957262
1998 Using chimeric MC1/MC3 receptors constructed by PCR-based domain swapping, transmembrane domains TM1, TM2, TM3, and TM7 were identified as contributors to subtype-specific binding of melanocortin peptides; TM4 and TM5 do not appear to contribute to ligand-binding specificity. Chimeric receptor construction, saturation and competition radioligand binding studies in expressed chimeric proteins Molecular pharmacology Medium 9658201
1999 Asp10 in gamma2-MSH determines MC3R selectivity over MC4R: substitution of Gly10 for Asp10 in Lys-gamma2-MSH selectively increased MC4R activity, while removal of Asp10 from the alpha-MSH analog selectively decreased MC4R EC50. Analysis of chimeric MC3R/MC4R and mutant MC4R (Tyr268Ile) showed Tyr268 of MC4R primarily determines low affinity for the Asp10-containing peptide; the mechanism involves conformational presentation of the core sequence rather than direct side-chain contact. Chimeric MC3R/MC4R receptor construction, site-directed mutagenesis of MC4R Tyr268, cAMP functional assays, ligand substitution studies The Journal of biological chemistry High 10358030
2000 D-amino acid substitution scan of gamma-MSH identified DTrp8 as a critical residue conferring ~300-fold selectivity for human MC3R over MC4R and MC5R (IC50 = 6 nM; EC50 = 0.33 nM at MC3R), establishing DTrp8-gamma-MSH as the most MC3R-selective agonist reported at that time. Radioligand binding competition assay and intracellular cAMP accumulation assay at human MC3R, MC4R, and MC5R for systematic D-amino acid substituted gamma-MSH analogs Journal of medicinal chemistry High 11150170
2001 MC3R and MC4R show differential G protein coupling efficiency: MC4R exhibits only 30–50% of the maximum cAMP-responsive gene transcription activity induced by MC3R. Additionally, MC3R stimulates significant inositol phosphate (IP) production in response to melanocortin peptides, whereas MC4R produces no detectable IP increase, indicating that MC3R couples to both Gs (cAMP) and Gq (phospholipid) pathways while MC4R couples only to Gs. Luciferase reporter gene under CRE control in HEK 293T cells transfected with MC3R or MC4R; inositol phosphate production assay European journal of biochemistry Medium 11168397
2002 The third intracellular (i3) loop domain of MC3R/MC4R determines differential G-protein coupling efficiency. Chimeric receptor analysis pinpointed the i3 loop as essential; single mutations of Arg220Ala and Thr232Val/Ala in the MC4R i3 loop increased luciferase reporter activity to MC3R-like levels. MC3R, but not any MC4R mutant tested, stimulates IP production, confirming MC3R-specific coupling to inositol phospholipid signaling. Chimeric MC3R/MC4R receptor construction, site-directed mutagenesis, CRE-luciferase reporter assay, inositol phosphate production assay in HEK 293T cells The Journal of biological chemistry High 12045190
2003 Mutation of MC4R Ile125 (TM3) to the equivalent MC3R residue (Phe) decreased affinity and potency of MC4R-selective ligands, and the reciprocal MC3R mutation Phe157Ile reduced MC3R selectivity, identifying TM3 position 125/157 as a determinant of MC4R/MC3R ligand selectivity, likely through indirect effects on Asp122 orientation. Site-directed mutagenesis of MC4R and MC3R, radioligand binding, functional cAMP assay The Journal of pharmacology and experimental therapeutics Medium 12604699
2002 MC3R mediates the protective effect of melanocortins against myocardial ischemia/reperfusion-induced arrhythmias in rats: selective MC3R agonist gamma1-MSH reduced ventricular tachycardia, ventricular fibrillation, and death; protection was blocked by MC3/4R antagonist SHU9119 but not by selective MC4R antagonist HS014 or MC1R agonist MS05, and persisted after adrenalectomy. In vivo rat ischemia/reperfusion model with pharmacological agonist/antagonist dissection; adrenalectomy controls Naunyn-Schmiedeberg's archives of pharmacology Medium 12122505
2004 MC3R is expressed at the protein level in mouse and rat heart macrophages (but not fibroblasts or cardiomyocytes), as shown by immunogold labeling. MC3R activation by MTII prior to or at onset of reperfusion attenuated myocardial injury (~40% reduction) and reduced markers of local and systemic inflammation (IL-1, KC cytokines, myeloperoxidase); this protection was lost with MC3/4R antagonist SHU9119 but not selective MC4R antagonist HS204, and was preserved in recessive yellow (e/e) mice bearing an inactive MC1R. Immunogold labeling for subcellular/cell-type localization; in vivo mouse ischemia/reperfusion model with pharmacological dissection; cytokine and myeloperoxidase measurements Journal of leukocyte biology Medium 15277567
2005 Peripheral injection of the MC3R-selective agonist D-Trp8-gamma-MSH stimulates feeding in mice, providing the first evidence that peripheral administration of a MC3R-specific agonist acts to increase food intake, consistent with MC3R functioning as an inhibitory autoreceptor on POMC neurons in the arcuate nucleus. Peripheral injection of peptidergic MC3R-specific agonist in mice with food intake measurement; receptor specificity inferred from use of MC3R-selective compound Peptides Medium 16274853
2005 Children homozygous for the double MC3R variant (Thr6Lys + Val81Ile) showed partial receptor inactivation: significantly fewer receptor binding sites, decreased cAMP signal transduction, and reduced MC3R protein expression in vitro compared with wild-type MC3R, establishing a functional mechanism linking these variants to greater body fat and obesity. In vitro expression studies with radioligand binding, cAMP assay, and protein expression measurement for WT and double-mutant MC3R Diabetes Medium 16123355
2008 MC3R is expressed on alveolar macrophages (but not other lung cell types tested) and mediates anti-inflammatory effects in lung: selective MC3R agonist [D-TRP8]-gamma-MSH increased cAMP in wild-type macrophages and recessive yellow (e/e; MC1R-inactive) macrophages but not in MC3R-null macrophages. In allergic and LPS-induced lung inflammation models, alpha-MSH and [D-TRP8]-gamma-MSH inhibited leukocyte accumulation and TNF-alpha release in wild-type and MC1R-mutant mice but not in MC3R-null mice. Western blot for MC1R/MC3R expression on alveolar macrophages; cAMP assay in isolated macrophages; in vivo allergic and LPS lung inflammation models in WT, e/e, and MC3R-null mice Pulmonary pharmacology & therapeutics High 18992358
2009 MC4R, but not MC3R, is required for melanocortin agonist-induced weight loss and food intake reduction: peripherally administered melanocortin agonists failed to reduce body weight in MC4R-KO mice but still reduced fasting insulin (~50%), indicating that MC4R mediates anorectic/weight-loss effects while other melanocortin receptors (potentially MC3R) may mediate improvements in glucose homeostasis. Treatment of MC3R-KO, MC4R-KO, and WT C57BL/6J mice with peripherally administered melanocortin agonists; measurement of body weight, food intake, insulin, and hepatic lipid/gene expression Peptides Medium 19646498
2014 MC3R is required for the full expression of food anticipatory activity (FAA) during restricted feeding: Mc3rKO mice showed persistently attenuated FAA and did not compensate over time (unlike GhsrKO mice). Absence of MC3R was associated with lower hypothalamic AgRP/NPY mRNA expression 1 hour before scheduled feeding, suggesting MC3R modulates FAA partly through regulation of AgRP/NPY orexigenic signaling. Behavioral testing of MC3R-KO, GHSR-KO, and double-KO mice under hypocaloric restricted feeding; hypothalamic AgRP/Npy mRNA measurement by qRT-PCR Endocrinology Medium 25211592
2016 Knock-in mice expressing the human double-mutant MC3R (C17A+G241A, corresponding to Thr6Lys+Val81Ile) have greater weight, fat mass, feeding efficiency, and reduced linear growth and fat-free mass compared to mice expressing wild-type human MC3R. MC3R(hDM/hDM) mice and human subjects have increased serum adiponectin. Bone- and adipose-derived mesenchymal stem cells from MC3R(hDM/hDM) mice accumulate more triglyceride upon adipocyte differentiation, pointing to a role for MC3R in nutrient partitioning and adipose development. Homozygous knock-in mouse models; body composition, metabolic, serum adiponectin, and adipocyte differentiation assays; comparison between hWT and hDM MC3R mice Nature communications High 26818770
2017 Chicken MC3R and MC4R co-immunoprecipitate with chicken MRAP2 (and MRAP), and co-expression with MRAP2 increases receptor sensitivity to ACTH, shifting pharmacology toward ACTH-preferring responses. AgRP acts as both an inverse agonist of cMC3R/cMC4R constitutive activity and an antagonist of ACTH/alpha-MSH-stimulated signaling. Both cMC3R and cMC4R display constitutive activity in CHO cells measurable by dual-luciferase reporter assay. Co-immunoprecipitation for MC3R–MRAP2 interaction; pGL3-CRE-luciferase reporter assay for receptor activation and constitutive activity; pharmacological characterization in CHO cells The Journal of endocrinology Medium 28512117
2019 Lateral hypothalamic MC3R-expressing (Mc3RLHA) neurons project to brain areas controlling feeding, locomotion, and energy expenditure. Chemogenetic activation of Mc3RLHA neurons increased locomotor activity and augmented refeeding after a fast. Selective ablation of Mc3RLHA neurons decreased energy expenditure and locomotor activity and increased body mass and adiposity, without altering food intake. Mc3rcre mouse generation; Cre-dependent viral circuit tracing; chemogenetic (DREADD) activation; cell-specific ablation; indirect calorimetry, locomotor activity, and body composition measurements Endocrinology High 30541071
2021 MC3R regulates timing of sexual maturation, rate of linear growth, and accrual of lean mass in an energy-sensitive manner: humans with loss-of-function MC3R mutations (including a rare homozygote) have later puberty onset, reduced linear growth, lean mass, and IGF1 levels. Mc3r-null mice show delayed sexual maturation and insensitivity of reproductive cycle length to nutritional perturbation. MC3R expression is enriched in hypothalamic neurons controlling reproduction/growth and increases during postnatal development. Human genetic study of MC3R loss-of-function carriers; Mc3r-null mouse phenotyping including reproductive timing and nutritional challenge; in situ hybridization/expression analysis of Mc3r in hypothalamus Nature High 34732894
2023 MC3R-expressing neurons in the paraventricular thalamus (PVT) receive direct innervation from hypothalamic AgRP and POMC neurons and are activated by anorexigenic and aversive stimuli. Chemogenetic activation of PVT MC3R neurons increases anxiety-related behavior and reduces feeding in hungry mice; inhibition reduces anxiety-related behavior. This positions PVT MC3R neurons as a circuit node linking energy status to anxiety regulation. Neuroanatomical tract tracing; in vivo calcium imaging; chemogenetic (DREADD) activation and inhibition of PVT MC3R neurons in Mc3rcre mice; anxiety and feeding behavioral assays The Journal of neuroscience High 37591737
2023 Loss-of-function variants in MC3R are overrepresented in patients with constitutional delay of growth and puberty (CDGP; 2.2% vs ~0.5% in controls, OR=4.17, P=0.001), but not in normosmic idiopathic hypogonadotropic hypogonadism, supporting a specific role for MC3R signaling in the tempo of pubertal development. MC3R sequencing in CDGP and nIHH patient cohorts; functional characterization of nonsynonymous variants for signaling properties; comparison to population controls from UK Biobank The Journal of clinical endocrinology and metabolism Medium 37339320
2006 Double in situ hybridization in rat arcuate nucleus showed that 38% of NPY mRNA-positive neurons express MC3R mRNA, while only 9% express MC4R mRNA, demonstrating that MC3R is the predominant melanocortin receptor on arcuate NPY neurons and suggesting alpha-MSH can directly modulate NPY neuron activity mainly through MC3R. Double-label in situ hybridization histochemistry with 35S-labeled MC3R/MC4R and digoxigenin-labeled NPY riboprobes in rat hypothalamus Neuroendocrinology Medium 16508337
2013 MC3R deletion facilitates MTII's protective effects against binge-like ethanol drinking: MC3R-KO mice were more sensitive to all doses of centrally administered MTII in reducing binge ethanol intake compared to WT mice, indicating that MC3R opposes the MC4R-mediated protective effects of MTII on binge drinking. Intracerebroventricular MTII administration in MC3R-/- and WT mice using 'drinking in the dark' binge ethanol protocol; blood ethanol concentration measurement Neuropeptides Medium 24290566
2012 MC3R expressed in human bronchial epithelial cells mediates anti-inflammatory effects of gamma-MSH: MC3R is expressed apically in airway epithelium in vivo, and gamma-MSH activation of MC3R suppresses TNFα- and RSV-evoked NFκB signaling, MMP-9 activity, IL-8, and eotaxin secretion in a receptor-dependent manner. NFκB reporter gene assay, chemokine ELISA, RT-PCR for MC3R, and competition/antagonist assays in immortalized human bronchial epithelial cells (16HBE14o-); in vivo immunostaining for MC3R distribution International journal of physiology, pathophysiology and pharmacology Medium 22837805

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochemical and biophysical research communications 195 9299416
1999 Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding. Diabetes 125 10334300
2002 A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. The Journal of clinical endocrinology and metabolism 110 11889220
2000 D-Amino acid scan of gamma-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity. Journal of medicinal chemistry 110 11150170
2022 Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells. Molecular pharmaceutics 109 35642083
2021 MC3R links nutritional state to childhood growth and the timing of puberty. Nature 108 34732894
2005 Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity. Diabetes 94 16123355
2005 The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R). Peptides 92 16274853
2003 Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity. The Journal of pharmacology and experimental therapeutics 73 12604699
2009 Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides 71 19646498
2008 Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis. American journal of respiratory and critical care medicine 67 18420963
1994 Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mammalian genome : official journal of the International Mammalian Genome Society 66 7949735
2008 Agouti-related peptide and MC3/4 receptor agonists both inhibit excitatory hypothalamic ventromedial nucleus neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 18495877
2005 Serotonin 5-HT7 receptors coupled to induction of interleukin-6 in human microglial MC-3 cells. Neuropharmacology 65 15992579
2000 Differential effects of melanocortin peptides on ingestive behaviour in rats: evidence against the involvement of MC(3) receptor in the regulation of food intake. Neuroscience letters 60 10729619
1998 Autoradiographic discrimination of melanocortin receptors indicates that the MC3 subtype dominates in the medial rat brain. Brain research 60 9813305
2008 A role for MC3R in modulating lung inflammation. Pulmonary pharmacology & therapeutics 59 18992358
2000 Melanocortin 3 receptor (MC3R) gene variants in extremely obese women. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 59 10702772
2020 DOPC versus DOPE as a helper lipid for gene-therapies: molecular dynamics simulations with DLin-MC3-DMA. Physical chemistry chemical physics : PCCP 57 33295352
1994 Identification of antagonists for melanocortin MC3, MC4 and MC5 receptors. European journal of pharmacology 57 7895772
2004 Cloning of two melanocortin (MC) receptors in spiny dogfish: MC3 receptor in cartilaginous fish shows high affinity to ACTH-derived peptides while it has lower preference to gamma-MSH. European journal of biochemistry 56 15511238
1999 Conformation of the core sequence in melanocortin peptides directs selectivity for the melanocortin MC3 and MC4 receptors. The Journal of biological chemistry 51 10358030
2017 The interaction of MC3R and MC4R with MRAP2, ACTH, α-MSH and AgRP in chickens. The Journal of endocrinology 48 28512117
2011 Physiological roles of the melanocortin MC₃ receptor. European journal of pharmacology 46 21211527
2010 Mutations in the melanocortin-3 receptor (MC3R) gene: Impact on human obesity or adiposity. Current opinion in investigational drugs (London, England : 2000) 45 20882712
2001 Differential regulation of cAMP-mediated gene transcription and ligand selectivity by MC3R and MC4R melanocortin receptors. European journal of biochemistry 44 11168397
2003 Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors. European journal of pharmacology 42 14522361
2002 Identification of domains directing specificity of coupling to G-proteins for the melanocortin MC3 and MC4 receptors. The Journal of biological chemistry 40 12045190
2007 Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout mice. Obesity (Silver Spring, Md.) 39 18070757
2010 Effect of MTII on food intake and brain c-Fos in melanocortin-3, melanocortin-4, and double MC3 and MC4 receptor knockout mice. Peptides 37 20800636
2004 MC-3 receptor and the inflammatory mechanisms activated in acute myocardial infarct. Journal of leukocyte biology 37 15277567
2001 PLS modeling of chimeric MS04/MSH-peptide and MC1/MC3-receptor interactions reveals a novel method for the analysis of ligand-receptor interactions. Biochimica et biophysica acta 37 11341944
2012 MC4R dimerization in the paraventricular nucleus and GHSR/MC3R heterodimerization in the arcuate nucleus: is there relevance for body weight regulation? Neuroendocrinology 36 22327910
2005 Novel 3D pharmacophore of alpha-MSH/gamma-MSH hybrids leads to selective human MC1R and MC3R analogues. Journal of medicinal chemistry 36 15771429
1998 Different developmental patterns of melanocortin MC3 and MC4 receptor mRNA: predominance of Mc4 in fetal rat nervous system. Journal of neuroendocrinology 35 9535059
1994 The melanocortin (MC3) receptor from rat hypothalamus: photoaffinity labelling and binding of alanine-substituted alpha-MSH analogues. FEBS letters 35 8062918
2011 Polymorphisms in MC3R promoter and CTSZ 3'UTR are associated with tuberculosis susceptibility. European journal of human genetics : EJHG 32 21368909
2010 Baicalin induces human mucoepidermoid carcinoma Mc3 cells apoptosis in vitro and in vivo. Investigational new drugs 32 20204673
2010 High-fat intake induced by mu-opioid activation of the nucleus accumbens is inhibited by Y1R-blockade and MC3/4R- stimulation. Brain research 32 20346352
2006 Expression of melanocortin MC3 and MC4 receptor mRNAs by neuropeptide Y neurons in the rat arcuate nucleus. Neuroendocrinology 32 16508337
2002 MC(3) receptors are involved in the protective effect of melanocortins in myocardial ischemia/reperfusion-induced arrhythmias. Naunyn-Schmiedeberg's archives of pharmacology 32 12122505
2013 Association of CTSZ rs34069356 and MC3R rs6127698 gene polymorphisms with pulmonary tuberculosis. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease 30 23827504
2016 A mouse model for a partially inactive obesity-associated human MC3R variant. Nature communications 28 26818770
2000 MC3-R as a novel target for antiinflammatory therapy. Drug news & perspectives 28 12937649
2019 Lateral Hypothalamic Mc3R-Expressing Neurons Modulate Locomotor Activity, Energy Expenditure, and Adiposity in Male Mice. Endocrinology 27 30541071
1998 Chimeric melanocortin MC1 and MC3 receptors: identification of domains participating in binding of melanocyte-stimulating hormone peptides. Molecular pharmacology 25 9658201
2016 Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently. ACS chemical neuroscience 24 27385405
2007 Silencing of CXCR4 inhibits the proliferation, adhesion, chemotaxis and invasion of salivary gland mucoepidermoid carcinoma Mc3 cells in vitro. Oral oncology 24 17936060
2011 Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets. PloS one 23 21695122
2022 Chrysin Induces Apoptosis via the MAPK Pathway and Regulates ERK/mTOR-Mediated Autophagy in MC-3 Cells. International journal of molecular sciences 21 36555388
2020 Arrayed CRISPR Screening Identifies Novel Targets That Enhance the Productive Delivery of mRNA by MC3-Based Lipid Nanoparticles. SLAS discovery : advancing life sciences R & D 21 32441189
2013 Fucoidan induces caspase-dependent apoptosis in MC3 human mucoepidermoid carcinoma cells. Experimental and therapeutic medicine 21 24348795
2003 Structure-activity relationships of gamma-MSH analogues at the human melanocortin MC3, MC4, and MC5 receptors. Discovery of highly selective hMC3R, hMC4R, and hMC5R analogues. Journal of medicinal chemistry 21 14584947
2023 DLin-MC3-Containing mRNA Lipid Nanoparticles Induce an Antibody Th2-Biased Immune Response Polarization in a Delivery Route-Dependent Manner in Mice. Pharmaceutics 19 36986871
2014 Assessing interactions between Ghsr and Mc3r reveals a role for AgRP in the expression of food anticipatory activity in male mice. Endocrinology 19 25211592
2010 γ₂-Melanocyte stimulation hormone (γ₂-MSH) truncation studies results in the cautionary note that γ₂-MSH is not selective for the mouse MC3R over the mouse MC5R. Peptides 19 20833220
1993 Drosophila proteasome Dm25 subunit substitutes the mouse MC3 subunit in hybrid proteasomes. The N-terminal domain is essential for subunit incorporation. The Journal of biological chemistry 19 8244993
2006 The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model. Peptides 18 16414147
2015 MC3R gene polymorphisms are associated with early childhood adiposity gain and infant appetite in an Asian population. Pediatric obesity 17 26663875
2014 Reversible hyperphagia and obesity in rats with gastric bypass by central MC3/4R blockade. Obesity (Silver Spring, Md.) 17 24799258
2012 The effect of melanocortin (Mc3 and Mc4) antagonists on serotonin-induced food and water intake of broiler cockerels. Journal of veterinary science 17 23000579
2014 Chronic central nervous system MC3/4R blockade attenuates hypertension induced by nitric oxide synthase inhibition but not by angiotensin II infusion. Hypertension (Dallas, Tex. : 1979) 16 25287400
2013 The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice. Neuropeptides 16 24290566
2008 Identification and distribution of thioredoxin-like 2 as the antigen for the monoclonal antibody MC3 specific to colorectal cancer. Proteomics 16 18528843
2023 Kaempferol induces apoptosis through the MAPK pathway and regulates JNK-mediated autophagy in MC-3 cells. Toxicological research 14 38223666
2020 Novel anti-inflammatory and chondroprotective effects of the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride and human melanocortin MC3 receptor agonist PG-990 on lipopolysaccharide activated chondrocytes. European journal of pharmacology 14 32004526
1995 Establishment and characterization of a new Ph1-positive chronic myeloid leukemia cell line MC3 with trilineage phenotype and an altered p53 gene. Leukemia & lymphoma 14 7787756
2014 Leptin in association with common variants of MC3R mediates hypertension. American journal of hypertension 13 24487982
2011 Association of MC3R gene polymorphisms with body weight in the red fox and comparative gene organization in four canids. Animal genetics 13 20477806
1995 Thirteen genes (Cebpb, E2f1, Tcf4, Cyp24, Pck1, Acra4, Edn3, Kcnb1, Mc3r, Ntsr, Cd40, Plcg1 and Rcad) that probably lie in the distal imprinting region of mouse chromosome 2 are not monoallelically expressed. Genetical research 13 7781998
2013 Ardipusilloside I induces apoptosis by regulating Bcl-2 family proteins in human mucoepidermoid carcinoma Mc3 cells. BMC complementary and alternative medicine 12 24256941
2012 Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides: mechanism of KPV action and a role for MC3R agonists. International journal of physiology, pathophysiology and pharmacology 12 22837805
1998 Asp10 in Lys-gamma2-MSH determines selective activation of the melanocortin MC3 receptor. European journal of pharmacology 12 9726642
1997 Binding and biological activity of C-terminally modified melanocortin peptides: a comparison between their actions at rodent MC1 and MC3 receptors. Peptides 12 9357058
1993 Characterization of mouse proteasome subunit MC3 and identification of proteasome subtypes with different cleavage characteristics. Proteasome subunits, proteasome subpopulations. Enzyme & protein 12 7697131
2022 Specific Functions of Melanocortin 3 Receptor (MC3R). Journal of clinical research in pediatric endocrinology 11 36053086
2018 Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists. Journal of medicinal chemistry 11 30035543
2017 Role of Reactive Oxygen Species during Low-Intensity Pulsed Ultrasound Application in MC-3 T3 E1 Pre-osteoblast Cell Culture. Ultrasound in medicine & biology 11 28807447
2013 Common polymorphism (81Val>Ile) and rare mutations (257Arg>Ser and 335Ile>Ser) of the MC3R gene in obese Polish children and adolescents. Molecular biology reports 11 24142065
2012 Prevalence of rare MC3R variants in obese cases and lean controls. Endocrine 11 23264184
2004 Change in CCK-8 response after diet-induced obesity and MC3/4-receptor blockade. Peptides 11 15063012
2023 Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty. The Journal of clinical endocrinology and metabolism 10 37339320
2019 Discovery of Polypharmacological Melanocortin-3 and -4 Receptor Probes and Identification of a 100-Fold Selective nM MC3R Agonist versus a μM MC4R Partial Agonist. Journal of medicinal chemistry 10 30741545
2016 In silico approach to identify non-synonymous SNPs in human obesity related gene, MC3R (melanocortin-3-receptor). Computational biology and chemistry 10 28073065
2014 Pycnogenol Induces Nuclear Translocation of Apoptosis-inducing Factor and Caspase-independent Apoptosis in MC-3 Human Mucoepidermoid Carcinoma Cell Line. Journal of cancer prevention 10 25574461
1996 Alternative translation initiation codon for the human melanocortin MC3 receptor does not affect the ligand binding. European journal of pharmacology 10 8957262
2023 Paraventricular Thalamic MC3R Circuits Link Energy Homeostasis with Anxiety-Related Behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 9 37591737
2019 Generation of an MC3R knock-out pig by CRSPR/Cas9 combined with somatic cell nuclear transfer (SCNT) technology. Lipids in health and disease 9 31138220
2019 Hypothalamic nesfatin-1 mediates feeding behavior via MC3/4R-ERK signaling pathway after weight loss in obese Sprague-Dawley rats. Peptides 9 31260713
2013 MC3: a steady-state model and constraint consistency checker for biochemical networks. BMC systems biology 9 24261865
2004 Evidence that the effect of melanocortins on female sexual behavior in preoptic area is mediated by the MC3 receptor; Participation of nitric oxide. Behavioural brain research 9 15265652
2011 Negative association of MC3R variants with weight and blood pressure in Cape Town pupils aged 11 - 16 years. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 8 21920079
2023 Influence of polymorphisms in IRS1, IRS2, MC3R, and MC4R on metabolic and inflammatory status and food intake in Brazilian adults: An exploratory pilot study. Nutrition research (New York, N.Y.) 7 37716291
2014 MC3 Mucoepidermoid carcinoma cell line enriched cancer stem-like cells following chemotherapy. Oncology letters 7 24765178
1995 Megakaryocytic differentiation of a leukemic cell line, MC3, by phorbol ester: induction of glycoprotein IIb/IIIa and effects on expression of IL-6, IL-6 receptor, mpl and GATA genes. Leukemia research 7 8632663
2023 Evaluation of the MC3R gene pertaining to body weight and height regulation and puberty development. Scientific reports 6 37369769
2021 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 6 33886285
2012 Cancer stem cell-like cells exist in mucoepidermoid carcinoma cell line MC3. Oncology research 6 24139417
2002 Expression and identification of recombinant soluble single-chain variable fragment of monoclonal antibody MC3. World journal of gastroenterology 6 11925603
2018 Association between Two Common Missense Substitutions, Thr6Lys and Val81Ile, in MC3R Gene and Childhood Obesity: A Meta-Analysis. Childhood obesity (Print) 5 29688747

Missed literature

Know a paper Affinage missed for MC3R? Flag it for the maintainers and the community.

No submissions yet.