Affinage

MC5R

Melanocortin receptor 5 · UniProt P33032

Length
325 aa
Mass
36.6 kDa
Annotated
2026-04-28
23 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC5R is a G protein-coupled melanocortin receptor that couples to adenylate cyclase/cAMP, PI3K/AKT, and MAPK signaling pathways and functions across diverse tissues to regulate immune tolerance, hematopoietic recovery, glucose homeostasis, and complement regulation (PMID:10687856, PMID:36920787, PMID:40739753). In splenic antigen-presenting cells, MC5R is required upstream of the adenosine 2A receptor to expand CD39⁺CD73⁺ regulatory APCs that drive FoxP3⁺ regulatory T cell activation via the adenosinergic pathway during recovery from experimental autoimmune uveitis (PMID:21989727, PMID:24043903, PMID:27886238). MC5R mediates α-MSH-induced glucose uptake in skeletal muscle and modulates glucose transporter balance in cardiomyocytes through PI3K signaling (PMID:30416452), and in podocytes it suppresses complement amplification by inhibiting factors B and D expression via a PPARγ-dependent mechanism, conferring protection against membranous nephropathy (PMID:40739753). Cell surface delivery of MC5R requires N-terminal Ser4/Ser5 and Ser17/Glu18 motifs for anterograde ER-to-plasma-membrane trafficking (PMID:28396017).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 Low

    Establishing that MC5R is a functional Gs-coupled receptor expressed in steroidogenic tissue resolved its basic signaling mode: ligand binding activates adenylate cyclase and its expression is hormonally regulated.

    Evidence RT-PCR, RNase protection assay, and cAMP assay in primary bovine adrenocortical cells

    PMID:10687856

    Open questions at the time
    • Expression-level study without direct mechanistic dissection
    • No loss-of-function evidence for adrenal function
    • Downstream effectors beyond cAMP not addressed
  2. 2010 Medium

    Systematic structure–activity analysis at cloned mouse versus human MC5R revealed species-specific ligand selectivity determinants (Arg7-Trp8 critical for rodent nM potency), establishing that pharmacological findings in rodents cannot be directly extrapolated to human MC5R.

    Evidence Pharmacological characterization of cloned mouse and human MC5R with truncated γ₂-MSH analogs, in vivo NDP-MSH treatment

    PMID:20833220

    Open questions at the time
    • No structural basis for species difference resolved
    • Functional consequences of species selectivity in vivo not tested
  3. 2011 Medium

    Genetic loss-of-function demonstrated that MC5R is required specifically on antigen-presenting cells — not T cells — to promote regulatory T cell activation during autoimmune uveitis recovery, establishing MC5R as an immune-regulatory receptor on APCs.

    Evidence Adoptive transfer of WT versus MC5r⁻/⁻ APCs and T cells in EAU mouse model, flow cytometry for FoxP3⁺TGF-β⁺ Tregs

    PMID:21989727

    Open questions at the time
    • Ligand identity in vivo not established
    • Intracellular signaling in APCs downstream of MC5R not defined
  4. 2013 Medium

    Dual-knockout epistasis placed MC5R upstream of the adenosine 2A receptor and identified CD39⁺CD73⁺ regulatory APCs as the MC5R-dependent intermediary cell population, revealing the adenosinergic pathway as the effector arm of MC5R-mediated immune regulation.

    Evidence MC5r⁻/⁻ and A2Ar⁻/⁻ mouse models with adoptive transfer and flow cytometry in EAU

    PMID:24043903

    Open questions at the time
    • Direct MC5R signaling events that induce CD39/CD73 expression unknown
    • Whether this pathway operates outside the eye/spleen axis not tested
  5. 2016 Medium

    Pharmacological A2Ar stimulation could not bypass MC5R deficiency, confirming the obligate hierarchical relationship where MC5R acts upstream of A2Ar to polarize distinct T cell programs.

    Evidence Cytokine profiling in MC5r⁻/⁻ and A2Ar⁻/⁻ mice with pharmacological A2Ar agonism during EAU

    PMID:27886238

    Open questions at the time
    • Molecular link between MC5R activation and A2Ar pathway induction still undefined
    • Single-lab replication
  6. 2017 Medium

    Mutagenesis of the MC5R N-terminus identified Ser4/Ser5 and Ser17/Glu18 as essential motifs for ER-to-plasma-membrane trafficking, separating the receptor's trafficking determinants from its ability to homodimerize.

    Evidence N-terminal deletion and site-directed mutagenesis with fluorescence imaging of ER/Golgi versus plasma membrane localization

    PMID:28396017

    Open questions at the time
    • Chaperones or coat-protein interactions mediating the trafficking step not identified
    • Relevance of these motifs in native tissues not verified
  7. 2018 Medium

    MC5R agonism in cardiomyocytes exposed to high glucose counteracted hypertrophy, shifted the GLUT1/GLUT4 membrane ratio, and increased PI3K activity, linking MC5R to glucose transporter regulation and metabolic signaling beyond cAMP.

    Evidence Pharmacological agonism (α-MSH, PG-901) in H9c2 cells, PI3K activity assay, glucose transporter quantification, diabetic rat echocardiography

    PMID:30416452

    Open questions at the time
    • MC5R specificity not confirmed by knockout or knockdown in cardiomyocytes
    • Relationship between PI3K activation and GLUT4 translocation not mechanistically dissected
  8. 2023 Medium

    MC5R knockout aggravated irradiation-induced myelosuppression and α-MSH treatment accelerated hematopoietic recovery via PI3K/AKT and MAPK, establishing MC5R as a proliferative signal for hematopoietic stem cells after injury.

    Evidence MC5R⁻/⁻ mouse irradiation model, pathway inhibitor assays, α-MSH treatment, bone marrow reconstitution

    PMID:36920787

    Open questions at the time
    • Cell-intrinsic versus niche-mediated HSC effects not resolved
    • Downstream transcriptional targets in HSCs unknown
  9. 2025 High

    Podocyte-specific MC5R reconstitution in knockout mice restored melanocortin efficacy against membranous nephropathy, and the mechanism was mapped to PPARγ-dependent suppression of complement factors B and D, revealing a cell-autonomous anti-complement function.

    Evidence Podocyte-specific MC5R reconstitution in MC5R⁻/⁻ mice, THSD7A nephropathy model, complement cascade analysis, cultured podocytes with PG-901

    PMID:40739753

    Open questions at the time
    • How MC5R activates PPARγ is not defined
    • Whether this complement-suppressive role extends to other glomerular diseases not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The intracellular signaling cascade linking MC5R activation to PPARγ engagement in podocytes, to CD39/CD73 induction in APCs, and to GLUT4 translocation in muscle remain undefined; no structural model of MC5R exists to explain species-specific ligand selectivity.
  • No crystal or cryo-EM structure of MC5R
  • Downstream signaling integration across cAMP, PI3K/AKT, and MAPK not mapped in any single cell type
  • Whether MC5R homo/heterodimerization is functionally relevant in mammalian physiology is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 1
Partners
CFBCFDMC1RPPARG

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 MC5R and MC1R from barfin flounder form heterodimers at the plasma membrane, and co-expression of bfMC1R with bfMC5R inhibits cAMP accumulation induced by α-MSH in a ligand-dependent manner (α-MSH but not desacetyl-α-MSH causes inhibition), demonstrating ligand-selective signaling through functional heterodimerization. Co-immunoprecipitation, immunofluorescence co-localization, cAMP accumulation assay in CHO cells General and comparative endocrinology Medium 27080548
2017 Cell surface targeting of MC5R requires serine-rich motifs in its N-terminal domain; specifically, residues Ser4/Ser5 and Ser17/Glu18 are necessary for anterograde trafficking from the ER/Golgi to the plasma membrane, while homodimerization is maintained in trafficking-deficient mutants. N-terminal deletion analysis, site-directed mutagenesis, fluorescence microscopy of ER/Golgi versus plasma membrane localization Biochimica et biophysica acta. Molecular cell research Medium 28396017
2011 MC5R expression is required on antigen-presenting cells (APCs), not on T cells, to promote activation of IRBP-specific FoxP3+TGF-β+CD25+CD4+ regulatory T cells in the spleens of EAU-recovering mice; APCs from wild-type but not MC5r-/- mice induced TGF-β expression in primed effector T cells. Adoptive transfer, flow cytometry, ELISA; wild-type vs. MC5r-/- mouse model with reciprocal APC/T-cell transfers Investigative ophthalmology & visual science Medium 21989727
2013 MC5r-dependent regulatory immunity in the spleen of post-EAU mice requires both MC5r expression on APCs and adenosine 2A receptor (A2Ar) expression on T cells; MC5r-dependent APCs expand CD11b+F4/80+Ly-6C(low)Ly-6G+CD39+CD73+ regulatory APCs that activate FoxP3+CD25+CD4+ Tregs via the adenosinergic pathway. MC5r-/- and A2Ar-/- mouse models, flow cytometry, adoptive transfer, in vivo EAU model Journal of immunology Medium 24043903
2016 MC5r and A2Ar mediate distinct T cell polarization programs during EAU; A2Ar stimulation at EAU onset cannot bypass the MC5r requirement to induce regulatory immunity, placing MC5r upstream of A2Ar in the regulatory immune pathway. Cytokine profile analysis, MC5r-/- and A2Ar-/- mouse models, pharmacological A2Ar stimulation during EAU Scientific reports Medium 27886238
2023 The melanocortin/MC5R axis regulates proliferation and reconstitution of hematopoietic stem cells (HSCs) after irradiation injury by activating the PI3K/AKT and MAPK signaling pathways; MC5R knockout aggravates irradiation-induced myelosuppression, and α-MSH treatment accelerates hematopoietic recovery. MC5R knockout mouse model, irradiation injury model, pathway inhibitor assays (PI3K/AKT and MAPK), α-MSH treatment, bone marrow reconstitution assay Blood advances Medium 36920787
2018 MC5R stimulation with α-MSH or selective agonist PG-901 in high-glucose-exposed H9c2 cardiomyocytes reduces hypertrophy, decreases the GLUT1/GLUT4 ratio on cell membranes, increases intracellular PI3K activity, and decreases miR-133a levels. Pharmacological agonism in H9c2 cell culture model, cell viability, protein quantification, glucose transporter ratio measurement, PI3K activity assay, miRNA quantification, STZ-diabetic rat echocardiography Frontiers in physiology Medium 30416452
2025 MC5R mediates α-MSH-induced glucose uptake in skeletal muscle; peripheral α-MSH or selective MC5R agonist PG-901 reduces blood glucose during glucose tolerance tests in rodents, non-human primates, and humans, and PG-901 induces glucose uptake in primary human myotubes in vitro; this effect is absent in MC5R-deficient mice. MC5R knockout mouse model, glucose tolerance tests in mice/NHP/humans, in vitro glucose uptake assay in primary human and NHP myotubes, selective MC5R agonist PG-901 bioRxiv (preprint)preprint High bio_10.1101_2025.03.26.645414
2025 Podocyte-expressed MC5R protects against membranous nephropathy by inhibiting podocyte expression of complement factors B and D (key regulators of the complement amplification loop) via a PPARγ-dependent mechanism; podocyte-specific reconstitution of MC5R in MC5R-knockout mice restores melanocortin therapeutic efficacy. MC5R knockout mouse model, podocyte-specific MC5R reconstitution, complement cascade analysis (C3, C5b-9, C4, factors B and D), cultured podocytes, selective MC5R agonist PG-901, THSD7A membranous nephropathy model Molecular therapy High 40739753
2000 MC5-R is expressed selectively in the glomerulosa zone of bovine adrenal cortex and its mRNA is upregulated by ACTH, α-MSH, and angiotensin II; MC5-R activates adenylate cyclase upon ligand binding. Semi-quantitative RT-PCR, RNase protection assay, primary adrenocortical cell culture with hormonal treatments Molecular and cellular endocrinology Low 10687856
2010 Species-specific differences exist in ligand potency at rodent versus human MC5R: γ₂-MSH analogs show nM potency at mouse MC5R but μM potency at human MC5R; Arg7-Trp8 residues are important for mMC5R nM potency; peripherally administered NDP-MSH decreases hypothalamic MC5R mRNA expression. Pharmacological characterization at cloned mouse and human MC5R, structure-activity relationship peptide truncation studies, in vivo NDP-MSH treatment with hypothalamic mRNA quantification Peptides Medium 20833220

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice. Journal of immunology (Baltimore, Md. : 1950) 64 24043903
2011 Following EAU recovery there is an associated MC5r-dependent APC induction of regulatory immunity in the spleen. Investigative ophthalmology & visual science 35 21989727
2017 Evolution of the MC5R gene in placental mammals with evidence for its inactivation in multiple lineages that lack sebaceous glands. Molecular phylogenetics and evolution 28 29277542
2008 Modeling the evolution of the MC2R and MC5R genes: studies on the cartilaginous fish, Heterondotus francisci. General and comparative endocrinology 28 19100739
2016 MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response. Scientific reports 27 27886238
2016 Dimerization of melanocortin receptor 1 (MC1R) and MC5R creates a ligand-dependent signal modulation: Potential participation in physiological color change in the flounder. General and comparative endocrinology 21 27080548
2018 The Melanocortin MC5R as a New Target for Treatment of High Glucose-Induced Hypertrophy of the Cardiac H9c2 Cells. Frontiers in physiology 20 30416452
1995 Localization of the human melanocortin-5 receptor gene (MC5R) to chromosome band 18p11.2 by fluorescence in situ hybridization. Cytogenetics and cell genetics 20 7956366
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
1999 Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima indians. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 17 10078851
1998 Expression of ACTH receptors (MC2-R and MC5-R) in the glomerulosa and the fasciculata-reticularis zones of bovine adrenal cortex. Endocrine research 16 9888520
2000 Expression and regulation of melanocortin receptor-5 (MC5-R) in the bovine adrenal cortex. Molecular and cellular endocrinology 12 10687856
2023 Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury. Blood advances 9 36920787
2023 Study on the Mechanism of MC5R Participating in Energy Metabolism of Goose Liver. International journal of molecular sciences 7 37239994
2022 Differential MC5R loss in whales and manatees reveals convergent evolution to the marine environment. Development genes and evolution 6 35648215
2017 Cell surface targeting of the Melanocortin 5 Receptor (MC5R) requires serine-rich terminal motifs. Biochimica et biophysica acta. Molecular cell research 6 28396017
2022 Analyzing the Hypothalamus/Pituitary/Interrenal axis of the neopterygian fish, Lepisosteus oculatus: Co-localization of MC2R, MC5R, MRAP1, and MRAP2 in interrenal cells. General and comparative endocrinology 4 35447133
2002 Expression of the melanocortin receptors MC2-R (ACTH-receptor) and MC5-R during embryonic development of ovine adrenals. Endocrine research 4 12530674
2025 Intercepting the complement amplification loop through podocyte MC5R signaling ameliorates membranous nephropathy. Molecular therapy : the journal of the American Society of Gene Therapy 3 40739753
2023 Discovery of a Pan-Melanocortin Receptor Antagonist [Ac-DPhe(pI)-Arg-Nal(2')-Orn-NH2] at the MC1R, MC3R, MC4R, and MC5R that Mediates an Increased Feeding Response in Mice and a 40-Fold Selective MC1R Antagonist [Ac-DPhe(pI)-DArg-Nal(2')-Arg-NH2]. Journal of medicinal chemistry 3 37307241
2021 MC5R Contributes to Sensitivity to UVB Waves and Barrier Function in Mouse Epidermis. JID innovations : skin science from molecules to population health 3 34909724
2025 From MC1R to MC5R, a new horizon for the podoprotective effect of melanocortin. Kidney international 0 40254355
2020 Molecular cloning and expression analysis of mc5r like genes (mc5rl) in Ruditapes philippinarum (Manila clam) after aerial exposure and low-temperature stress. Molecular biology reports 0 33128687