Affinage

MC5R

Melanocortin receptor 5 · UniProt P33032

Length
325 aa
Mass
36.6 kDa
Annotated
2026-06-10
23 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC5R is a melanocortin G protein-coupled receptor that couples α-MSH and related melanocortin ligands to cAMP and PI3K/AKT/MAPK signaling to control diverse peripheral cellular responses (PMID:36920787, PMID:10687856). Its activity is set at the cell surface: delivery of MC5R to the plasma membrane requires two N-terminal serine-rich motifs (Ser4/Ser5 and Ser17/Glu18), and mutation of these residues traps the receptor at the ER/Golgi, a process independent of its capacity to dimerize (PMID:28396017). MC5R can engage other melanocortin receptors physically, forming heterodimers with MC1R that confer ligand-dependent suppression of cAMP signaling (PMID:27080548). Functionally, MC5R operates as a cell-autonomous effector across tissues: on antigen-presenting cells it drives adenosinergic induction of FoxP3+ regulatory T cells via A2A receptor signaling to enforce ocular regulatory immunity (PMID:21989727, PMID:24043903); in skeletal muscle it mediates melanocortin-driven glucose uptake [PMID:bio_10.1101_2025.03.26.645414]; in podocytes it suppresses complement factors B and D through a PPARγ-dependent mechanism to intercept the complement amplification loop in membranous nephropathy (PMID:40739753); and it supports hematopoietic stem cell proliferation after irradiation through PI3K/AKT and MAPK activation (PMID:36920787). MC5R is also required for epidermal barrier integrity and lamellar granule-mediated lipid secretion (PMID:34909724). No structural model of human MC5R or its signaling complex is characterized in the available corpus.

Mechanistic history

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

    Established that MC5R is expressed and hormonally regulated in a defined adrenal compartment, indicating a peripheral, ligand-responsive receptor rather than a purely central one.

    Evidence Semi-quantitative RT-PCR and RNase protection in bovine adrenal glomerulosa primary cells with ACTH/α-MSH/angiotensin II treatment

    PMID:10687856

    Open questions at the time
    • Expression measured by semi-quantitative methods only
    • No downstream signaling or functional consequence defined
    • Restricted to bovine adrenal tissue
  2. 2011 Medium

    Resolved which cell type requires MC5R for melanocortin-driven regulatory immunity, showing the receptor acts in APCs rather than T cells.

    Evidence MC5r-/- mice, APC isolation, co-culture cytokine assays and adoptive transfer in post-EAU spleen

    PMID:21989727

    Open questions at the time
    • Signaling pathway downstream of MC5R in APCs not defined
    • Ligand driving APC MC5R activation in vivo not identified
  3. 2013 Medium

    Identified the effector pathway linking APC MC5R to Treg induction, defining a CD39/CD73 adenosinergic axis requiring T-cell A2A receptor.

    Evidence MC5r-/- and A2Ar-/- mouse epistasis, flow cytometry phenotyping, Treg induction assays

    PMID:24043903

    Open questions at the time
    • Molecular link between MC5R signaling and CD39/CD73 expression not established
    • Generality beyond ocular autoimmunity untested
  4. 2016 Medium

    Demonstrated MC5R forms heterodimers with another melanocortin receptor, providing a mechanism for ligand-selective modulation of cAMP output.

    Evidence Reciprocal Co-IP, co-localization, and cAMP accumulation assays in CHO cells using barfin flounder MC1R/MC5R

    PMID:27080548

    Open questions at the time
    • Shown in fish orthologs; conservation in mammalian MC5R not tested
    • Stoichiometry and structural basis of the heterodimer unknown
  5. 2017 Medium

    Mapped the determinants of MC5R cell surface delivery, separating trafficking control from dimerization.

    Evidence N-terminal deletion, site-directed mutagenesis (Ser4/Ser5, Ser17/Glu18), and ER/Golgi vs plasma membrane imaging

    PMID:28396017

    Open questions at the time
    • Trafficking chaperones or machinery recognizing the N-terminal motifs not identified
    • Effect of mutations on downstream signaling not quantified
  6. 2021 Medium

    Revealed an MC5R requirement in epidermal homeostasis, linking the receptor to lipid secretion, barrier formation, and UVB-stress responses.

    Evidence MC5R knockout mice with transepidermal water loss, TEM ultrastructure, and cytokine measurement

    PMID:34909724

    Open questions at the time
    • Signaling pathway in keratinocytes not defined
    • Mechanism connecting MC5R to lamellar granule biogenesis unknown
  7. 2023 Medium

    Defined a melanocortin/MC5R role in hematopoietic regeneration through PI3K/AKT and MAPK signaling.

    Evidence MC5R knockout plus irradiation injury model with pathway inhibitors, α-MSH rescue, and reconstitution assays

    PMID:36920787

    Open questions at the time
    • Direct receptor-effector coupling in HSCs not biochemically resolved
    • Whether effect is HSC-intrinsic or niche-mediated not fully separated
  8. 2025 High

    Established podocyte MC5R as the cell-autonomous effector suppressing complement factors B and D via PPARγ, defining a therapeutic mechanism in membranous nephropathy.

    Evidence MC5R knockout with podocyte-specific reconstitution, selective agonist PG-901, complement and PPARγ pathway analysis

    PMID:40739753

    Open questions at the time
    • Molecular link between MC5R signaling and PPARγ activation not detailed
    • Whether the same axis operates in human disease not established
  9. 2025 Medium

    Demonstrated MC5R mediates peripheral α-MSH-driven glucose uptake in skeletal muscle across species including humans.

    Evidence MC5R knockout mice, selective agonist PG-901 in glucose tolerance tests, glucose uptake in primary human/NHP myotubes, human OGTT (preprint)

    PMID:bio_10.1101_2025.03.26.645414

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Intracellular signaling driving glucose uptake in myotubes not defined
    • GLUT transporter mechanism not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single melanocortin receptor coordinates such diverse tissue-specific outputs (immune, metabolic, renal, epidermal, hematopoietic) through distinct downstream effectors remains unresolved.
  • No unifying signaling logic linking MC5R to cell-type-specific effectors (PPARγ, adenosinergic, GLUT, PI3K)
  • No structural model of human MC5R or its complexes
  • Endogenous ligand and bias determinants per tissue not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
MC1R

Evidence

Reading pass · 10 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. Co-immunoprecipitation showed bfMC1R and bfMC5R physically interact, and heterodimerization produces ligand-dependent inhibition of cAMP accumulation: α-MSH-induced cAMP was suppressed by coexpression of both receptors, whereas desacetyl-α-MSH was not inhibitory. This provides a mechanism for selective pigment dispersion in different chromatophore types. Co-immunoprecipitation, immunofluorescence co-localization, cAMP accumulation assay in CHO cells General and comparative endocrinology Medium 27080548
2017 Cell surface targeting of MC5R requires two serine-rich motifs in the N-terminal domain (residues Ser4/Ser5 and Ser17/Glu18). Site-directed mutagenesis of these residues caused retention of MC5R at the ER/Golgi complex rather than delivery to the plasma membrane. The first 21 amino acids contain the information required for correct trafficking, and homodimerization was unaffected by these mutations, indicating that surface targeting and dimerization are independent processes. N-terminal deletion analysis, site-directed mutagenesis, fluorescence microscopy of ER/Golgi vs. plasma membrane localization Biochimica et biophysica acta. Molecular cell research Medium 28396017
2011 MC5R expression is required on APCs (not T cells) to promote regulatory immunity in the spleen of EAU-recovering mice. APCs from wild-type EAU-recovering mice induced TGF-β expression and FoxP3+CD25+CD4+ Treg cell activation in IRBP-specific effector T cells from MC5r-/- mice, whereas APCs from MC5r-/- mice failed to do so. Adoptive transfer confirmed the APC-intrinsic dependence on MC5r. MC5r-/- mouse model, APC isolation, co-culture cytokine assays (ELISA, flow cytometry), adoptive transfer Investigative ophthalmology & visual science Medium 21989727
2013 MC5r-dependent regulatory immunity in post-EAU spleen requires adenosine 2A receptor (A2Ar) expression on T cells. MC5r-dependent APCs were identified as CD11b+F4/80+Ly-6C(low)Ly-6G+CD39+CD73+ cells, and these APCs use the adenosinergic pathway to activate autoantigen-specific FoxP3+CD25+CD4+ regulatory T cells. Both MC5r and A2Ar are required for EAU-suppressing regulatory immunity. MC5r-/- and A2Ar-/- mouse models, flow cytometry, functional assays of Treg induction Journal of immunology Medium 24043903
2023 The melanocortin/MC5R axis regulates proliferation of hematopoietic stem cells (HSCs) after irradiation via activation of the PI3K/AKT and MAPK signaling pathways. MC5R knockout aggravated irradiation-induced myelosuppression due to impaired HSC proliferation and reconstitution, and α-MSH treatment accelerated hematopoietic recovery in irradiated mice. MC5R knockout mouse model, irradiation injury model, pathway inhibitor assays (PI3K/AKT, MAPK), α-MSH treatment, colony/reconstitution assays Blood advances Medium 36920787
2025 Peripheral α-MSH promotes glucose uptake in skeletal muscle via an MC5R-dependent mechanism. A selective MC5R agonist (PG-901) reduced blood glucose during a glucose tolerance test in wild-type mice but had no effect in MC5R-deficient mice. Both α-MSH and PG-901 directly induced glucose uptake in primary human and non-human primate myotubes in vitro, and the pathway was functional in healthy human volunteers. MC5R knockout mouse model, glucose tolerance test, in vitro glucose uptake assay in primary human myotubes, human oral glucose tolerance test with α-MSH administration bioRxivpreprint Medium bio_10.1101_2025.03.26.645414
2025 Podocyte MC5R intercepts the complement amplification loop in membranous nephropathy by inhibiting podocyte expression of complement factors B and D via a PPARγ-dependent mechanism. MC5R knockout exacerbated glomerular C5b-9 and C3 fixation, whereas MC5R agonism diminished it. Podocyte-specific reconstitution of MC5R in MC5R knockout mice restored melanocortin therapeutic efficacy, establishing podocyte MC5R as the critical cell-autonomous effector. MC5R knockout mouse model, podocyte-specific MC5R reconstitution, selective MC5R agonist (PG-901), complement cascade analysis, PPARγ pathway analysis, cultured podocyte assays Molecular therapy High 40739753
2018 MC5R stimulation in high-glucose-exposed cardiac H9c2 cells reduces hypertrophy by activating PI3K signaling and decreasing the GLUT1/GLUT4 ratio on the cell membrane, mediated by a reduction in miR-133a levels. MC5R agonist (α-MSH, PG-901) treatment of H9c2 cells, PI3K activity assay, GLUT1/GLUT4 quantification, miR-133a measurement, streptozotocin-diabetic rat echocardiography Frontiers in physiology Low 30416452
2000 MC5-R in bovine adrenal glomerulosa cells is upregulated by ACTH, α-MSH, and angiotensin II (7-, 5-, and 4.5-fold respectively) at the mRNA level, and MC5-R is expressed exclusively in the glomerulosa zone (not fasciculata) of adult adrenal cortex, at levels at least 100-fold lower than MC2-R. Semi-quantitative RT-PCR, RNase protection assay, primary adrenocortical cell culture with hormone treatment Molecular and cellular endocrinology Low 10687856
2021 MC5R deficiency in mice leads to impaired epidermal barrier function, characterized by increased transepidermal water loss, fewer lamellar granules, reduced lipid secretion, and expansion of the trans-Golgi network in epidermal cells. MC5R-deficient mice also showed increased UVB sensitivity with enhanced inflammatory cell infiltration and elevated IL-6 but reduced IL-10. MC5R knockout mouse model, transepidermal water loss measurement, dye exclusion assay, transmission electron microscopy, cytokine measurement JID innovations Medium 34909724

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
2008 Modeling the evolution of the MC2R and MC5R genes: studies on the cartilaginous fish, Heterondotus francisci. General and comparative endocrinology 29 19100739
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
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 8 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 5 35447133
2025 Intercepting the complement amplification loop through podocyte MC5R signaling ameliorates membranous nephropathy. Molecular therapy : the journal of the American Society of Gene Therapy 4 40739753
2002 Expression of the melanocortin receptors MC2-R (ACTH-receptor) and MC5-R during embryonic development of ovine adrenals. Endocrine research 4 12530674
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

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