Affinage

MC3R

Melanocortin receptor 3 · UniProt P41968

Length
323 aa
Mass
36.0 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC3R is a melanocortin receptor that functions as a nutrient-state sensor, coupling energy availability to growth, body composition, pubertal timing, locomotor activity, and anticipatory behavior rather than acute food intake regulation. Activated preferentially by γ-MSH and antagonized by AgRP and MRAP2, MC3R signals through both Gs/cAMP and Gq/phospholipase C pathways, with the third intracellular loop and transmembrane domains TM1–TM3/TM7 governing subtype-selective ligand recognition and G-protein coupling efficiency (PMID:11168397, PMID:12045190, PMID:9658201). MC3R operates as an inhibitory autoreceptor on arcuate POMC neurons to stimulate feeding, drives locomotor activity and energy expenditure via lateral hypothalamic neurons, and links energy status to anxiety-related behavior through paraventricular thalamic neurons (PMID:16274853, PMID:30541071, PMID:37591737). Loss-of-function MC3R mutations in humans cause delayed puberty, reduced linear growth, diminished lean mass, and lower circulating IGF1, while in peripheral macrophages MC3R mediates anti-inflammatory cardioprotective and pulmonary protective effects of melanocortins (PMID:34732894, PMID:15277567, PMID:18992358).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1994 High

    Defining the pharmacophore: the conserved melanocortin core (Met-X-His-Phe-Arg-Trp) was shown to be critical for MC3R ligand recognition, with Met4, Phe7, Arg8, and Trp9 essential and Glu5 dispensable, establishing the molecular basis of ligand binding.

    Evidence Photoaffinity labeling and alanine-scan competitive binding at cloned rat MC3R

    PMID:8062918

    Open questions at the time
    • No receptor-side residue identification at this stage
    • Binding determinants for non-α-MSH ligands not tested
  2. 1994 High

    Pharmacological separation of MC3R from MC4R/MC5R was achieved using subtype-selective peptide antagonists, demonstrating that α-MSH-induced grooming is MC4R-mediated and establishing MC3R as functionally distinct in vivo.

    Evidence cAMP assays in HEK293 cells expressing MC3R/MC4R/MC5R plus in vivo grooming behavior with selective antagonists in rats

    PMID:7895772

    Open questions at the time
    • Endogenous MC3R-specific behavioral readout not yet identified
    • No MC3R knockout available to confirm
  3. 1997 High

    AgRP (ART) was identified as a potent endogenous antagonist of MC3R (and MC4R) with ~100-fold selectivity over MC5R, establishing the agonist-antagonist framework for melanocortin signaling at MC3R.

    Evidence Competitive radioligand binding and cAMP assays in COS-7 cells expressing human MC3R, MC4R, MC5R

    PMID:9299416

    Open questions at the time
    • Inverse agonist activity of AgRP at MC3R not tested at this point
    • In vivo relevance of AgRP–MC3R antagonism unresolved
  4. 1998 High

    Receptor-side determinants of subtype selectivity were mapped: TM1, TM2, TM3, and TM7 govern ligand-binding differences between MC1R and MC3R, and the Asp10 residue in γ-MSH confers MC3R selectivity over MC4R.

    Evidence Chimeric MC1R/MC3R receptors with binding assays; peptide mutagenesis with cAMP assays at MC3R vs MC4R

    PMID:9658201 PMID:9726642

    Open questions at the time
    • No crystal/cryo-EM structure to confirm spatial arrangement
    • Residue-level contacts between ligand and receptor not resolved
  5. 1999 High

    A specific TM6 residue (Tyr268 in MC4R, distinct in MC3R) was shown to control low affinity for γ-MSH ligands, revealing that MC3R/MC4R selectivity arises from ligand conformational effects rather than direct side-chain contacts.

    Evidence Chimeric MC3R/MC4R and Tyr268Ile mutagenesis with binding/cAMP assays

    PMID:10358030

    Open questions at the time
    • No structural validation of proposed conformational mechanism
  6. 2001 High

    MC3R was shown to couple to both Gs/cAMP and Gq/phospholipase C (inositol phosphate) pathways, whereas MC4R signals only through cAMP, revealing a qualitative signaling divergence between the two central melanocortin receptors.

    Evidence CRE-luciferase and inositol phosphate assays in HEK293T cells expressing MC3R or MC4R

    PMID:11168397

    Open questions at the time
    • Physiological relevance of IP signaling in neurons not established
    • Downstream effectors of MC3R-PLC pathway unknown
  7. 2002 High

    The third intracellular loop was identified as the structural determinant of differential G-protein coupling between MC3R and MC4R, with specific MC4R residues (Arg220, Thr232) suppressing coupling efficiency relative to MC3R.

    Evidence Chimeric MC3R/MC4R i3 loop constructs and point mutations with CRE-luciferase and IP assays in HEK293T cells

    PMID:12045190

    Open questions at the time
    • G-protein selectivity in native neurons not confirmed
    • β-arrestin coupling not examined
  8. 2002 High

    MC3R was established as the melanocortin receptor mediating cardioprotection during ischemia-reperfusion, with pharmacological dissection excluding MC1R and MC4R contributions.

    Evidence In vivo rat myocardial ischemia-reperfusion with γ1-MSH, SHU9119, HS014, MS05, and adrenalectomy

    PMID:12122505

    Open questions at the time
    • Signaling pathway downstream of MC3R in cardiac context unknown
    • Cell type expressing MC3R in heart not yet identified
  9. 2004 High

    MC3R protein was localized to heart macrophages (not cardiomyocytes) by immunogold labeling, resolving the cellular basis of MC3R-mediated cardioprotection and extending MC3R function to immune-resident cells.

    Evidence Immunogold EM in mouse heart; in vivo ischemia-reperfusion in MC1R-mutant and WT mice with MC3R/MC4R-selective agents

    PMID:15277567

    Open questions at the time
    • Macrophage-specific MC3R signaling mechanism not characterized
    • Contribution of other immune cells unclear
  10. 2005 High

    MC3R was proposed to function as an inhibitory autoreceptor on POMC neurons, explaining the paradoxical orexigenic effect of MC3R-selective agonists, and loss-of-function human MC3R variants (Thr6Lys+Val81Ile) were shown to reduce receptor expression and signaling, linking MC3R dysfunction to childhood adiposity.

    Evidence Peripheral d-Trp8-γ-MSH injection with feeding measurement in mice; radioligand binding, cAMP, and protein expression assays of mutant vs WT MC3R in vitro

    PMID:16123355 PMID:16274853

    Open questions at the time
    • Direct electrophysiological confirmation of autoreceptor function on POMC neurons needed
    • Population-level replication of human variant associations required
  11. 2006 Medium

    MC3R mRNA was found predominantly on arcuate NPY neurons (38% co-expression vs 9% for MC4R), establishing MC3R as the principal melanocortin receptor on orexigenic NPY/AgRP neurons.

    Evidence Double-label in situ hybridization in rat hypothalamus

    PMID:16508337

    Open questions at the time
    • Functional consequence of MC3R on NPY neurons not directly tested
    • Protein-level confirmation lacking
  12. 2008 High

    MC3R on alveolar macrophages was shown to be necessary for the anti-inflammatory actions of melanocortins in lung inflammation, using MC3R-null mice to definitively assign receptor identity.

    Evidence cAMP in WT/e-e/MC3R-null macrophages; in vivo allergic and LPS lung inflammation in MC3R-null mice

    PMID:18992358

    Open questions at the time
    • Downstream anti-inflammatory effectors not identified
    • Human pulmonary macrophage MC3R expression not confirmed
  13. 2008 High

    Direct electrophysiology demonstrated that MC3R agonists hyperpolarize glutamatergic VMH neurons, showing MC3R acts as an inhibitory receptor on excitatory hypothalamic neurons and revealing that AgRP inhibition at VMH uses a separate Gi/Go presynaptic mechanism.

    Evidence Whole-cell patch clamp in hypothalamic slices from vGluT2-GFP mice with selective MC3R agonists, SHU9119, AgRP, and pertussis toxin

    PMID:18495877

    Open questions at the time
    • Ion channel mediating MC3R-induced hyperpolarization not identified
    • In vivo behavioral consequence of VMH MC3R not established
  14. 2014 Medium

    MC3R was shown to be essential for food anticipatory activity (FAA) during restricted feeding, with Mc3r-null mice showing persistent FAA deficits and reduced hypothalamic AgRP/NPY expression, positioning MC3R as a circadian-metabolic integrator.

    Evidence Mc3rKO, GhsrKO, and double-KO mice under hypocaloric restricted feeding; AgRP/NPY mRNA quantification; locomotor monitoring

    PMID:25211592

    Open questions at the time
    • Neural circuit mediating MC3R-dependent FAA not mapped
    • Relationship between MC3R and clock gene machinery unknown
  15. 2016 High

    Humanized knock-in mice expressing double-mutant MC3R recapitulated increased adiposity, reduced lean mass, and enhanced MSC triglyceride accumulation, demonstrating MC3R directly influences nutrient partitioning and mesenchymal cell fate.

    Evidence MC3R(hDM/hDM) vs MC3R(hWT/hWT) knock-in mice; body composition, energy intake, ex vivo MSC differentiation

    PMID:26818770

    Open questions at the time
    • MC3R signaling pathway in MSCs not defined
    • Whether MC3R acts cell-autonomously in MSCs vs via systemic signals unclear
  16. 2019 High

    Circuit-level dissection showed that MC3R-expressing lateral hypothalamic neurons drive locomotor activity and energy expenditure but not food intake, establishing a discrete neuronal population through which MC3R controls energy output.

    Evidence Mc3r-Cre mice with viral tracing, DREADD activation/ablation of LHA MC3R neurons; metabolic phenotyping

    PMID:30541071

    Open questions at the time
    • Downstream projection targets mediating locomotor effects not fully resolved
    • Endogenous ligand dynamics at LHA MC3R neurons unknown
  17. 2021 High

    MC3R was established as a regulator of pubertal timing, linear growth, and lean mass accrual in humans and mice, with human loss-of-function MC3R mutations causing delayed puberty, short stature, and low IGF1, unifying MC3R's role as a nutrient sensor coupling energy state to developmental programs.

    Evidence Human genetic analysis of MC3R LoF carriers including rare homozygote; Mc3r-null mouse phenotyping; hypothalamic single-cell transcriptomics

    PMID:34732894

    Open questions at the time
    • Mechanism linking MC3R to GH/IGF1 axis not defined
    • Whether MC3R acts on GnRH neurons directly or indirectly unknown
  18. 2023 High

    MC3R-expressing PVT neurons were identified as an integration node receiving AgRP/POMC inputs and bidirectionally controlling anxiety-related behavior, revealing a non-metabolic behavioral axis of MC3R signaling.

    Evidence Neuroanatomical tracing; bidirectional DREADD manipulation of MC3R-PVT neurons; anxiety and feeding behavioral assays

    PMID:37591737

    Open questions at the time
    • Whether MC3R signaling (vs neuronal identity) drives the anxiety phenotype not dissected
    • Human relevance of PVT MC3R-anxiety link untested
  19. 2023 Medium

    Thermal proteome profiling after MC3R activation identified ~298 downstream proteins with altered thermal stability, including transcription factors CCAR2, DDX21, HMGB2, SRSF7, and TET2, providing the first proteome-wide map of the MC3R signaling cascade.

    Evidence Label-free TPP with LC-MS; phosphoproteomics validation in MC3R-expressing cells stimulated with ACTH, α-MSH, γ-MSH

    PMID:37804223

    Open questions at the time
    • Individual TF contributions to MC3R-dependent transcription not validated by loss-of-function
    • Overlap with MC4R downstream signaling not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of MC3R ligand selectivity (no high-resolution structure), the signaling pathway linking MC3R to IGF1/GH axis regulation, the ion channels mediating MC3R-dependent neuronal inhibition, and whether MC3R's PLC/IP pathway is physiologically relevant in neurons.
  • No cryo-EM or crystal structure of MC3R
  • MC3R-to-GH/IGF1 signaling mechanism undefined
  • Identity of ion channels downstream of MC3R in hypothalamic neurons unknown
  • In vivo relevance of Gq/PLC coupling not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1
Partners
AGRPGHSRMRAP2POMC

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ART (agouti-related transcript protein) functions as an antagonist of human MC3R and MC4R, inhibiting binding of radiolabeled alpha-MSH analog and blocking receptor activation, with approximately 100-fold greater potency at MC3R/MC4R than agouti; ART does not potently antagonize MC5R. Competitive radioligand binding assay and functional cAMP assay in COS-7 cells expressing human MC3R, MC4R, and MC5R Biochemical and biophysical research communications High 9299416
1994 The rat MC3 receptor is a ~53-56 kDa glycoprotein (35 kDa deglycosylated), and the conserved core sequence (Met-Glu/Gly-His-Phe-Arg-Trp) is critical for ligand recognition; residues Met4, Phe7, Arg8, and Trp9 within this core are essential for binding, while Glu5 is unimportant. Photoaffinity labeling with radiolabeled photoreactive alpha-MSH analog followed by SDS-PAGE; competitive binding assays with alanine-substituted alpha-MSH analogs at cloned rat MC3 receptor membranes FEBS letters High 8062918
1994 Distinct peptide antagonists discriminate MC3R from MC4R and MC5R: [D-Arg8]ACTH-(4-10) and [Pro8,10,Gly9]ACTH-(4-10) antagonize MC4R and MC5R but not MC3R; [Ala6]ACTH-(4-10) antagonizes MC3R and MC5R but only weakly MC4R; [Phe-I7]ACTH-(4-10) antagonizes all three receptors. Alpha-MSH-induced excessive grooming behavior is mediated by MC4R, not MC3R. cAMP accumulation assay in HEK293 cells expressing rat MC3R, human MC4R, or ovine MC5R; in vivo grooming behavior assay in rats with selective antagonists European journal of pharmacology High 7895772
1996 The unusually long N-terminus of human MC3R, specified by an upstream translation initiation codon, is not required for ligand binding; both the original and an alternate initiation site 111 bp downstream yield functional receptor with identical ligand-binding properties. Site-directed mutagenesis of initiation codons and deletion of intervening sequence, expressed in COS cells with radioligand binding assays European journal of pharmacology High 8957262
1998 Transmembrane domains TM1, TM2, TM3, and TM7 of MC1R and MC3R determine subtype-specific ligand binding; TM4 and TM5 do not contribute to ligand-binding selectivity between MC1R and MC3R. Chimeric MC1/MC3 receptor constructs (PCR-based domain swapping) expressed in cells, with saturation and competition binding studies Molecular pharmacology High 9658201
1998 Asp10 in Lys-gamma2-MSH determines selective activation of MC3R versus MC4R; introduction of Asp10 into [Nle4]alpha-MSH selectively increases EC50 at MC4R while MC3R remains unaffected; removal of Asp10 from [Nle4]Lys-gamma2-MSH selectively decreases EC50 at MC4R. Site-directed mutagenesis of peptide ligands with functional cAMP assays at MC3R and MC4R European journal of pharmacology High 9726642
1999 Tyr268 in TM6 of MC4R is a key determinant of low affinity for gamma-MSH-selective ligands; mutation Tyr268Ile in MC4R increases affinity for [Nle4]Lys-gamma2-MSH. The conformation of the melanocortin core sequence (influenced by Asp10) determines selectivity between MC3R and MC4R rather than direct side-chain interactions. Chimeric MC3R/MC4R receptors and site-directed mutagenesis of MC4R combined with binding and cAMP activity assays The Journal of biological chemistry High 10358030
2000 DTrp8 substitution in gamma-MSH yields a highly potent (EC50 = 0.33 nM) and ~250-300-fold selective MC3R agonist over MC4R and MC5R, establishing Trp8 and aromatic residues at positions 1, 6, and 11 and basic Arg10 (but not Arg7) as key determinants of MC3R selectivity. Systematic D-amino acid substitution scan of gamma-MSH with competitive radioligand binding and cAMP functional assays at human MC3R, MC4R, and MC5R Journal of medicinal chemistry High 11150170
2001 MC3R and MC4R differ quantitatively and qualitatively in G-protein coupling: MC4R shows only 30-50% of the maximum cAMP-mediated transcriptional activity induced by MC3R. Additionally, MC3R stimulates inositol phosphate (IP) production (phospholipase C pathway) in response to melanocortin peptides, whereas MC4R does not. CRE-luciferase reporter gene assay and inositol phosphate measurement in HEK293T cells transfected with MC3R or MC4R; NMR modeling of receptor-ligand complexes European journal of biochemistry High 11168397
2002 The third intracellular (i3) loop of MC4R is essential for the differential G-protein coupling efficiency between MC3R and MC4R. Specific residues Arg220 and Thr232 in the i3 loop of MC4R suppress its coupling efficiency relative to MC3R; single mutations R220A or T232V/A increase MC4R cAMP signaling. MC3R but not MC4R couples to inositol phospholipid signaling. Chimeric MC3R/MC4R constructs, site-directed mutagenesis of i3 loop residues, CRE-luciferase reporter gene assay, and inositol phosphate measurement in HEK293T cells The Journal of biological chemistry High 12045190
2003 Ile125 in TM3 of MC4R (equivalent to Phe157 in MC3R) contributes to subtype-selective ligand binding; Ile125Phe mutation in MC4R decreases affinity/potency of MC4R-selective ligands, and the reciprocal MC3R mutation Phe157Ile mirrors this effect. This locus modulates selectivity partly by influencing orientation of Asp122. Site-directed mutagenesis of MC4R and MC3R combined with radioligand binding and functional potency assays with diverse ligand panels The Journal of pharmacology and experimental therapeutics High 12604699
2002 MC3R activation mediates the cardioprotective effects of melanocortins in myocardial ischemia/reperfusion-induced arrhythmias in rats; selective MC3R agonist gamma1-MSH reduced ventricular tachycardia, fibrillation, and death; this protection was blocked by MC3/4R antagonist SHU9119 but not by selective MC4R antagonist HS014 or selective MC1R agonist MS05, and was independent of adrenal activation. In vivo rat myocardial ischemia/reperfusion model with selective receptor agonists/antagonists and adrenalectomy Naunyn-Schmiedeberg's archives of pharmacology High 12122505
2004 MC3R protein is expressed in heart macrophages (but not cardiomyocytes or fibroblasts) as shown by immunogold labeling; in vivo MC3R activation by MTII reduces acute and delayed myocardial reperfusion injury (~40%) in mice; this protection is blocked by MC3/4R antagonist SHU9119 but not by selective MC4R antagonist HS204, and is fully retained in MC1R-inactive (recessive yellow e/e) mice. Immunogold electron microscopy for cellular MC3R localization; in vivo mouse ischemia/reperfusion model with selective pharmacological agents and MC1R-mutant mice Journal of leukocyte biology High 15277567
2005 MC3R functions as an inhibitory autoreceptor on POMC neurons in the arcuate nucleus; peripheral injection of the MC3R-selective agonist d-Trp8-gamma-MSH stimulates feeding, consistent with inhibition of POMC neurons via MC3R. Peripheral peptide injection in mice with pharmacological selectivity established using MC3R-specific agonist d-Trp8-gamma-MSH; feeding behavior measurement Peptides Medium 16274853
2005 Homozygous double MC3R variant (Thr6Lys + Val81Ile) results in a partially inactive receptor with significantly fewer binding sites, decreased signal transduction (cAMP), and reduced protein expression compared to wild-type MC3R, associated with greater adiposity in children. In vitro expression studies: radioligand binding, cAMP functional assay, and protein expression analysis of wild-type vs. double-mutant MC3R; clinical phenotyping of variant-carrying children Diabetes High 16123355
2006 MC3R mRNA is expressed in 38% of NPY-expressing neurons in the rat arcuate nucleus, while only 9% express MC4R mRNA, indicating that alpha-MSH can directly modulate NPY neuron activity predominantly via MC3R. Double-label in situ hybridization histochemistry with 35S-labeled MC3R/MC4R and digoxigenin-labeled NPY riboprobes in rat hypothalamus Neuroendocrinology Medium 16508337
2008 MC3R expressed on alveolar macrophages mediates anti-inflammatory effects of melanocortins in allergic and non-allergic lung inflammation; selective MC3R agonist [D-TRP8]-gamma-MSH increases cAMP in wild-type and MC1R-inactive (e/e) macrophages but not in MC3R-null macrophages; alpha-MSH fails to inhibit eosinophil/lymphocyte accumulation or TNF-alpha release in MC3R-null mice. Western blot for MCR expression; cAMP assay in isolated alveolar macrophages from wild-type, e/e, and MC3R-null mice; in vivo allergic and LPS-induced lung inflammation models in MC3R-null mice with selective agonists Pulmonary pharmacology & therapeutics High 18992358
2008 MC3R and MC4R agonists both inhibit excitatory glutamatergic VMH neurons; selective MC3R agonists hyperpolarize vGluT2-expressing VMH neurons; MC3/4R antagonist SHU9119 excites these neurons; AgRP inhibition of VMH neurons operates via G(i)/G(o)-mediated presynaptic EPSC inhibition independent of MC receptor signaling (shown by pertussis toxin sensitivity and lack of attenuation by MTII). Whole-cell patch-clamp recording in hypothalamic slices from GFP-vGluT2 reporter mice; pharmacological application of selective MC3R/MC4R agonists, antagonists, AgRP; pertussis toxin and NF023 treatments The Journal of neuroscience High 18495877
2009 MC4R but not MC3R is required for melanocortin agonist-induced food intake reduction and weight loss; MC3R is not required for melanocortin-induced weight loss, but melanocortin receptors other than MC4R (potentially MC3R) may contribute to improvements in hyperinsulinemia independent of weight loss. MC3R knockout and MC4R knockout C57BL/6J mice treated with peripherally administered melanocortin receptor agonists BIM-22493 and BIM-22511; measurement of body weight, food intake, fasting insulin, hepatosteatosis Peptides High 19646498
2012 MC3R and growth hormone secretagogue receptor (GHSR)-1a physically interact (heterodimerize) in the arcuate nucleus, resulting in modulation of function of both receptors. Co-immunoprecipitation and functional characterization of GHSR/MC3R heterodimers in hypothalamic arcuate nucleus context (reviewed evidence) Neuroendocrinology Low 22327910
2014 MC3R is required for the normal expression of food anticipatory activity (FAA) during restricted feeding; Mc3r-null mice show persistent attenuation of FAA that cannot be compensated, whereas Ghsr-null mice eventually compensate. Reduced hypothalamic AgRP/NPY expression (correlating positively with FAA) in the absence of Mc3r suggests MC3R modulates anticipatory responses partly by regulating orexigenic AgRP/NPY neuron activity during negative energy balance. Mc3rKO, GhsrKO, and double-KO mouse comparison under hypocaloric restricted feeding protocols; AgRP/Npy mRNA quantification; locomotor activity monitoring Endocrinology Medium 25211592
2016 Homozygous knock-in mice expressing the human double-mutant MC3R (C17A+G241A) have greater fat mass, increased energy intake, reduced lean mass and length compared with mice expressing wild-type human MC3R; MC3R(hDM/hDM) bone- and adipose-derived mesenchymal stem cells accumulate more triglyceride, indicating a role for MC3R in adipose tissue development and nutrient partitioning. Homozygous knock-in mouse models (MC3R(hWT/hWT) vs. MC3R(hDM/hDM)); body composition analysis, energy intake measurement, ex vivo MSC differentiation assays, serum adiponectin measurement Nature communications High 26818770
2017 Chicken MC3R and MC4R co-immunoprecipitate with chicken MRAP2 (and MRAP); co-expression with MRAP2 increases sensitivity of cMC3R to ACTH treatment (ACTH-preferring receptor), modulates constitutive activity of cMC3R, and AgRP functions as inverse agonist reducing constitutive activity and as antagonist blocking ACTH/alpha-MSH action on cMC3R. Co-immunoprecipitation of cMC3R with cMRAP2; pGL3-CRE-luciferase reporter assay and dual-luciferase assay for constitutive activity in CHO cells The Journal of endocrinology Medium 28512117
2019 Lateral hypothalamic MC3R (Mc3RLHA) neurons project to brain areas controlling feeding, locomotion, and energy expenditure; chemogenetic activation of Mc3RLHA neurons increases locomotor activity and augments refeeding after fasting; ablation of Mc3RLHA neurons decreases energy expenditure and locomotor activity and increases body mass and adiposity without altering food intake. Mc3rcre mouse generation; viral tract tracing; chemogenetic (DREADD) activation and neuronal ablation with phenotypic readouts (locomotor activity, energy expenditure, body composition, food intake) Endocrinology High 30541071
2021 MC3R regulates the timing of sexual maturation, rate of linear growth, and accrual of lean mass in humans and mice; Mc3r-null mice have delayed sexual maturation and insensitivity of reproductive cycle length to nutritional perturbation; MC3R expression is enriched in hypothalamic neurons controlling reproduction and growth; human loss-of-function MC3R mutations are associated with later puberty onset, reduced linear growth, lean mass, and circulating IGF1. Human genetic analysis of MC3R loss-of-function carriers (including rare homozygote); Mc3r-null mouse phenotyping (puberty timing, reproductive cycle, body composition, IGF1); hypothalamic Mc3r expression analysis by single-cell transcriptomics and developmental profiling Nature High 34732894
2023 MC3R-expressing neurons in the paraventricular thalamus (PVT) are innervated by hypothalamic AgRP and POMC neurons; PVT MC3R neurons are activated by anorexigenic and aversive stimuli; chemogenetic activation increases anxiety-related behavior and reduces feeding in hungry mice, while inhibition reduces anxiety-related behavior, linking energy status sensing to anxiety circuit regulation. Neuroanatomical tracing; Cre-dependent viral chemogenetics (DREADD activation and inhibition) in MC3R-PVT neurons; behavioral assays for anxiety and feeding in mice The Journal of neuroscience High 37591737
2023 Thermal proteome profiling of cells after MC3R activation by ACTH, alpha-MSH, and gamma-MSH identified 298 proteins with altered thermal stability downstream of MC3R; transcription factors CCAR2, DDX21, HMGB2, SRSF7, and TET2 showed altered thermal stability, indicating their involvement in the MC3R signaling cascade; inferred transcription factor activities were validated by phosphorylated peptide abundances. Label-free quantitative thermal proteome profiling (TPP) with ion-mobility-enhanced LC-MS; gene set enrichment analysis; transcription factor activity inference with Bayesian statistics; phosphoproteomics validation Analytical chemistry Medium 37804223

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
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
2002 A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. The Journal of clinical endocrinology and metabolism 109 11889220
2021 MC3R links nutritional state to childhood growth and the timing of puberty. Nature 103 34732894
2022 Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells. Molecular pharmaceutics 100 35642083
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 91 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 68 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
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
2008 A role for MC3R in modulating lung inflammation. Pulmonary pharmacology & therapeutics 58 18992358
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
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
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 36 20800636
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
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
2006 Expression of melanocortin MC3 and MC4 receptor mRNAs by neuropeptide Y neurons in the rat arcuate nucleus. Neuroendocrinology 31 16508337
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
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
2022 Chrysin Induces Apoptosis via the MAPK Pathway and Regulates ERK/mTOR-Mediated Autophagy in MC-3 Cells. International journal of molecular sciences 19 36555388
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
2023 DLin-MC3-Containing mRNA Lipid Nanoparticles Induce an Antibody Th2-Biased Immune Response Polarization in a Delivery Route-Dependent Manner in Mice. Pharmaceutics 17 36986871
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
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
2023 Kaempferol induces apoptosis through the MAPK pathway and regulates JNK-mediated autophagy in MC-3 cells. Toxicological research 13 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 13 32004526
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
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
2016 In silico approach to identify non-synonymous SNPs in human obesity related gene, MC3R (melanocortin-3-receptor). Computational biology and chemistry 9 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 9 25574461
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
2023 Label-Free Quantitative Thermal Proteome Profiling Reveals Target Transcription Factors with Activities Modulated by MC3R Signaling. Analytical chemistry 5 37804223