{"gene":"MC5R","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence co-localization, cAMP accumulation assay in CHO cells","journal":"General and comparative endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional cAMP assay; single lab, teleost orthologs","pmids":["27080548"],"is_preprint":false},{"year":2017,"finding":"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.","method":"N-terminal deletion analysis, site-directed mutagenesis, fluorescence microscopy of ER/Golgi versus plasma membrane localization","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with direct localization imaging; single lab, multiple orthogonal constructs","pmids":["28396017"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Adoptive transfer, flow cytometry, ELISA; wild-type vs. MC5r-/- mouse model with reciprocal APC/T-cell transfers","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with adoptive transfer epistasis; single lab replicated across multiple papers","pmids":["21989727"],"is_preprint":false},{"year":2013,"finding":"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.","method":"MC5r-/- and A2Ar-/- mouse models, flow cytometry, adoptive transfer, in vivo EAU model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — dual genetic KO epistasis with defined cellular phenotypes; replicated across lab publications","pmids":["24043903"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Cytokine profile analysis, MC5r-/- and A2Ar-/- mouse models, pharmacological A2Ar stimulation during EAU","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with pharmacological intervention; single lab","pmids":["27886238"],"is_preprint":false},{"year":2023,"finding":"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.","method":"MC5R knockout mouse model, irradiation injury model, pathway inhibitor assays (PI3K/AKT and MAPK), α-MSH treatment, bone marrow reconstitution assay","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype and pathway identification; single lab","pmids":["36920787"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Pharmacological agonism in H9c2 cell culture model, cell viability, protein quantification, glucose transporter ratio measurement, PI3K activity assay, miRNA quantification, STZ-diabetic rat echocardiography","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal in vitro assays plus in vivo validation; single lab","pmids":["30416452"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1-2 — KO rescue, selective agonist, in vitro reconstitution in human cells, cross-species validation","pmids":["bio_10.1101_2025.03.26.645414"],"is_preprint":true},{"year":2025,"finding":"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.","method":"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","journal":"Molecular therapy","confidence":"High","confidence_rationale":"Tier 1-2 — KO plus cell-type-specific reconstitution, mechanistic pathway (PPARγ/complement factors B and D) identified with multiple orthogonal methods","pmids":["40739753"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Semi-quantitative RT-PCR, RNase protection assay, primary adrenocortical cell culture with hormonal treatments","journal":"Molecular and cellular endocrinology","confidence":"Low","confidence_rationale":"Tier 3 — expression and pharmacological assay without direct mechanistic dissection; single lab","pmids":["10687856"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Pharmacological characterization at cloned mouse and human MC5R, structure-activity relationship peptide truncation studies, in vivo NDP-MSH treatment with hypothalamic mRNA quantification","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 1-2 — systematic SAR with cloned receptors, in vitro pharmacology with mutagenic implications, replicated binding assays","pmids":["20833220"],"is_preprint":false}],"current_model":"MC5R is a G protein-coupled receptor that signals through cAMP/adenylate cyclase and PI3K/AKT and MAPK pathways; its cell surface targeting requires N-terminal Ser4/Ser5 and Ser17/Glu18 motifs for ER-to-plasma-membrane trafficking; it functions in skeletal muscle to mediate α-MSH-induced glucose uptake, in podocytes to suppress complement amplification via a PPARγ-dependent inhibition of factors B and D, in splenic APCs to promote regulatory T cell activation via the adenosinergic pathway during recovery from autoimmune uveitis, and in hematopoietic stem cells to support proliferative recovery after irradiation injury."},"narrative":{"teleology":[{"year":2000,"claim":"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","pmids":["10687856"],"confidence":"Low","gaps":["Expression-level study without direct mechanistic dissection","No loss-of-function evidence for adrenal function","Downstream effectors beyond cAMP not addressed"]},{"year":2010,"claim":"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","pmids":["20833220"],"confidence":"Medium","gaps":["No structural basis for species difference resolved","Functional consequences of species selectivity in vivo not tested"]},{"year":2011,"claim":"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","pmids":["21989727"],"confidence":"Medium","gaps":["Ligand identity in vivo not established","Intracellular signaling in APCs downstream of MC5R not defined"]},{"year":2013,"claim":"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","pmids":["24043903"],"confidence":"Medium","gaps":["Direct MC5R signaling events that induce CD39/CD73 expression unknown","Whether this pathway operates outside the eye/spleen axis not tested"]},{"year":2016,"claim":"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","pmids":["27886238"],"confidence":"Medium","gaps":["Molecular link between MC5R activation and A2Ar pathway induction still undefined","Single-lab replication"]},{"year":2017,"claim":"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","pmids":["28396017"],"confidence":"Medium","gaps":["Chaperones or coat-protein interactions mediating the trafficking step not identified","Relevance of these motifs in native tissues not verified"]},{"year":2018,"claim":"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","pmids":["30416452"],"confidence":"Medium","gaps":["MC5R specificity not confirmed by knockout or knockdown in cardiomyocytes","Relationship between PI3K activation and GLUT4 translocation not mechanistically dissected"]},{"year":2023,"claim":"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","pmids":["36920787"],"confidence":"Medium","gaps":["Cell-intrinsic versus niche-mediated HSC effects not resolved","Downstream transcriptional targets in HSCs unknown"]},{"year":2025,"claim":"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","pmids":["40739753"],"confidence":"High","gaps":["How MC5R activates PPARγ is not defined","Whether this complement-suppressive role extends to other glomerular diseases not tested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,6,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8]}],"complexes":[],"partners":["MC1R","PPARG","CFB","CFD"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P33032","full_name":"Melanocortin receptor 5","aliases":["MC-2"],"length_aa":325,"mass_kda":36.6,"function":"G protein-coupled receptor for melanocyte-stimulating hormones (alpha- beta- and gamma-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor (PubMed:37524700, PubMed:8396929). Upon activation, couples to G(s) protein, stimulating adenylate cyclase and the cAMP-dependent signaling pathway (PubMed:37524700). Also activates ERK1/2 via a PI3K-dependent signaling mechanism (PubMed:19428994). Order of potency of natural melanocortins in receptor activation is alpha-MSH > ACTH > beta-MSH > gamma-MSH (PubMed:8396929). Plays a key role in immune response, and is essential for temperature regulation and exocrine gland function (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P33032/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MC5R","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MC5R","total_profiled":1310},"omim":[{"mim_id":"600042","title":"MELANOCORTIN 5 RECEPTOR; MC5R","url":"https://www.omim.org/entry/600042"},{"mim_id":"102776","title":"ADENOSINE A2A RECEPTOR; ADORA2A","url":"https://www.omim.org/entry/102776"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"epididymis","ntpm":2.5},{"tissue":"lymphoid tissue","ntpm":1.0}],"url":"https://www.proteinatlas.org/search/MC5R"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P33032","domains":[{"cath_id":"1.20.1070.10","chopping":"35-306","consensus_level":"high","plddt":90.3511,"start":35,"end":306}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P33032","model_url":"https://alphafold.ebi.ac.uk/files/AF-P33032-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P33032-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MC5R","jax_strain_url":"https://www.jax.org/strain/search?query=MC5R"},"sequence":{"accession":"P33032","fasta_url":"https://rest.uniprot.org/uniprotkb/P33032.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P33032/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P33032"}},"corpus_meta":[{"pmid":"24043903","id":"PMC_24043903","title":"Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24043903","citation_count":64,"is_preprint":false},{"pmid":"21989727","id":"PMC_21989727","title":"Following EAU recovery there is an associated MC5r-dependent APC induction of regulatory immunity in the spleen.","date":"2011","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/21989727","citation_count":35,"is_preprint":false},{"pmid":"19100739","id":"PMC_19100739","title":"Modeling the evolution of the MC2R and MC5R genes: studies on the cartilaginous fish, Heterondotus francisci.","date":"2008","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19100739","citation_count":28,"is_preprint":false},{"pmid":"29277542","id":"PMC_29277542","title":"Evolution of the MC5R gene in placental mammals with evidence for its inactivation in multiple lineages that lack sebaceous glands.","date":"2017","source":"Molecular phylogenetics and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/29277542","citation_count":28,"is_preprint":false},{"pmid":"27886238","id":"PMC_27886238","title":"MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27886238","citation_count":27,"is_preprint":false},{"pmid":"27080548","id":"PMC_27080548","title":"Dimerization of melanocortin receptor 1 (MC1R) and MC5R creates a ligand-dependent signal modulation: Potential participation in physiological color change in the flounder.","date":"2016","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27080548","citation_count":21,"is_preprint":false},{"pmid":"30416452","id":"PMC_30416452","title":"The Melanocortin MC5R as a New Target for Treatment of High Glucose-Induced Hypertrophy of the Cardiac H9c2 Cells.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30416452","citation_count":20,"is_preprint":false},{"pmid":"7956366","id":"PMC_7956366","title":"Localization of the human melanocortin-5 receptor gene (MC5R) to chromosome band 18p11.2 by fluorescence in situ hybridization.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7956366","citation_count":20,"is_preprint":false},{"pmid":"20833220","id":"PMC_20833220","title":"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.","date":"2010","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/20833220","citation_count":19,"is_preprint":false},{"pmid":"10078851","id":"PMC_10078851","title":"Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima indians.","date":"1999","source":"International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity","url":"https://pubmed.ncbi.nlm.nih.gov/10078851","citation_count":17,"is_preprint":false},{"pmid":"9888520","id":"PMC_9888520","title":"Expression of ACTH receptors (MC2-R and MC5-R) in the glomerulosa and the fasciculata-reticularis zones of bovine adrenal cortex.","date":"1998","source":"Endocrine research","url":"https://pubmed.ncbi.nlm.nih.gov/9888520","citation_count":16,"is_preprint":false},{"pmid":"10687856","id":"PMC_10687856","title":"Expression and regulation of melanocortin receptor-5 (MC5-R) in the bovine adrenal cortex.","date":"2000","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10687856","citation_count":12,"is_preprint":false},{"pmid":"36920787","id":"PMC_36920787","title":"Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury.","date":"2023","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/36920787","citation_count":9,"is_preprint":false},{"pmid":"37239994","id":"PMC_37239994","title":"Study on the Mechanism of MC5R Participating in Energy Metabolism of Goose Liver.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37239994","citation_count":7,"is_preprint":false},{"pmid":"28396017","id":"PMC_28396017","title":"Cell surface targeting of the Melanocortin 5 Receptor (MC5R) requires serine-rich terminal motifs.","date":"2017","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28396017","citation_count":6,"is_preprint":false},{"pmid":"35648215","id":"PMC_35648215","title":"Differential MC5R loss in whales and manatees reveals convergent evolution to the marine environment.","date":"2022","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/35648215","citation_count":6,"is_preprint":false},{"pmid":"35447133","id":"PMC_35447133","title":"Analyzing the Hypothalamus/Pituitary/Interrenal axis of the neopterygian fish, Lepisosteus oculatus: Co-localization of MC2R, MC5R, MRAP1, and MRAP2 in interrenal cells.","date":"2022","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35447133","citation_count":4,"is_preprint":false},{"pmid":"12530674","id":"PMC_12530674","title":"Expression of the melanocortin receptors MC2-R (ACTH-receptor) and MC5-R during embryonic development of ovine adrenals.","date":"2002","source":"Endocrine research","url":"https://pubmed.ncbi.nlm.nih.gov/12530674","citation_count":4,"is_preprint":false},{"pmid":"40739753","id":"PMC_40739753","title":"Intercepting the complement amplification loop through podocyte MC5R signaling ameliorates membranous nephropathy.","date":"2025","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40739753","citation_count":3,"is_preprint":false},{"pmid":"34909724","id":"PMC_34909724","title":"MC5R Contributes to Sensitivity to UVB Waves and Barrier Function in Mouse Epidermis.","date":"2021","source":"JID innovations : skin science from molecules to population health","url":"https://pubmed.ncbi.nlm.nih.gov/34909724","citation_count":3,"is_preprint":false},{"pmid":"37307241","id":"PMC_37307241","title":"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].","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37307241","citation_count":3,"is_preprint":false},{"pmid":"40254355","id":"PMC_40254355","title":"From MC1R to MC5R, a new horizon for the podoprotective effect of melanocortin.","date":"2025","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/40254355","citation_count":0,"is_preprint":false},{"pmid":"33128687","id":"PMC_33128687","title":"Molecular cloning and expression analysis of mc5r like genes (mc5rl) in Ruditapes philippinarum (Manila clam) after aerial exposure and low-temperature stress.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33128687","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.26.645414","title":"α-Melanocyte Stimulating Hormone Reduces Blood Glucose Across Species","date":"2025-03-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.26.645414","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12710,"output_tokens":2762,"usd":0.03978},"stage2":{"model":"claude-opus-4-6","input_tokens":6155,"output_tokens":2509,"usd":0.14025},"total_usd":0.18003,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, cAMP accumulation assay in CHO cells\",\n      \"journal\": \"General and comparative endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional cAMP assay; single lab, teleost orthologs\",\n      \"pmids\": [\"27080548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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      \"method\": \"N-terminal deletion analysis, site-directed mutagenesis, fluorescence microscopy of ER/Golgi versus plasma membrane localization\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with direct localization imaging; single lab, multiple orthogonal constructs\",\n      \"pmids\": [\"28396017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Adoptive transfer, flow cytometry, ELISA; wild-type vs. MC5r-/- mouse model with reciprocal APC/T-cell transfers\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with adoptive transfer epistasis; single lab replicated across multiple papers\",\n      \"pmids\": [\"21989727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"MC5r-/- and A2Ar-/- mouse models, flow cytometry, adoptive transfer, in vivo EAU model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual genetic KO epistasis with defined cellular phenotypes; replicated across lab publications\",\n      \"pmids\": [\"24043903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Cytokine profile analysis, MC5r-/- and A2Ar-/- mouse models, pharmacological A2Ar stimulation during EAU\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with pharmacological intervention; single lab\",\n      \"pmids\": [\"27886238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"MC5R knockout mouse model, irradiation injury model, pathway inhibitor assays (PI3K/AKT and MAPK), α-MSH treatment, bone marrow reconstitution assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype and pathway identification; single lab\",\n      \"pmids\": [\"36920787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological agonism in H9c2 cell culture model, cell viability, protein quantification, glucose transporter ratio measurement, PI3K activity assay, miRNA quantification, STZ-diabetic rat echocardiography\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro assays plus in vivo validation; single lab\",\n      \"pmids\": [\"30416452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO rescue, selective agonist, in vitro reconstitution in human cells, cross-species validation\",\n      \"pmids\": [\"bio_10.1101_2025.03.26.645414\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO plus cell-type-specific reconstitution, mechanistic pathway (PPARγ/complement factors B and D) identified with multiple orthogonal methods\",\n      \"pmids\": [\"40739753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Semi-quantitative RT-PCR, RNase protection assay, primary adrenocortical cell culture with hormonal treatments\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression and pharmacological assay without direct mechanistic dissection; single lab\",\n      \"pmids\": [\"10687856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological characterization at cloned mouse and human MC5R, structure-activity relationship peptide truncation studies, in vivo NDP-MSH treatment with hypothalamic mRNA quantification\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic SAR with cloned receptors, in vitro pharmacology with mutagenic implications, replicated binding assays\",\n      \"pmids\": [\"20833220\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MC5R is a G protein-coupled receptor that signals through cAMP/adenylate cyclase and PI3K/AKT and MAPK pathways; its cell surface targeting requires N-terminal Ser4/Ser5 and Ser17/Glu18 motifs for ER-to-plasma-membrane trafficking; it functions in skeletal muscle to mediate α-MSH-induced glucose uptake, in podocytes to suppress complement amplification via a PPARγ-dependent inhibition of factors B and D, in splenic APCs to promote regulatory T cell activation via the adenosinergic pathway during recovery from autoimmune uveitis, and in hematopoietic stem cells to support proliferative recovery after irradiation injury.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"RT-PCR, RNase protection assay, and cAMP assay in primary bovine adrenocortical cells\",\n      \"pmids\": [\"10687856\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression-level study without direct mechanistic dissection\", \"No loss-of-function evidence for adrenal function\", \"Downstream effectors beyond cAMP not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pharmacological characterization of cloned mouse and human MC5R with truncated γ₂-MSH analogs, in vivo NDP-MSH treatment\",\n      \"pmids\": [\"20833220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for species difference resolved\", \"Functional consequences of species selectivity in vivo not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Adoptive transfer of WT versus MC5r⁻/⁻ APCs and T cells in EAU mouse model, flow cytometry for FoxP3⁺TGF-β⁺ Tregs\",\n      \"pmids\": [\"21989727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand identity in vivo not established\", \"Intracellular signaling in APCs downstream of MC5R not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"MC5r⁻/⁻ and A2Ar⁻/⁻ mouse models with adoptive transfer and flow cytometry in EAU\",\n      \"pmids\": [\"24043903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MC5R signaling events that induce CD39/CD73 expression unknown\", \"Whether this pathway operates outside the eye/spleen axis not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cytokine profiling in MC5r⁻/⁻ and A2Ar⁻/⁻ mice with pharmacological A2Ar agonism during EAU\",\n      \"pmids\": [\"27886238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between MC5R activation and A2Ar pathway induction still undefined\", \"Single-lab replication\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"N-terminal deletion and site-directed mutagenesis with fluorescence imaging of ER/Golgi versus plasma membrane localization\",\n      \"pmids\": [\"28396017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chaperones or coat-protein interactions mediating the trafficking step not identified\", \"Relevance of these motifs in native tissues not verified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pharmacological agonism (α-MSH, PG-901) in H9c2 cells, PI3K activity assay, glucose transporter quantification, diabetic rat echocardiography\",\n      \"pmids\": [\"30416452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MC5R specificity not confirmed by knockout or knockdown in cardiomyocytes\", \"Relationship between PI3K activation and GLUT4 translocation not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"MC5R⁻/⁻ mouse irradiation model, pathway inhibitor assays, α-MSH treatment, bone marrow reconstitution\",\n      \"pmids\": [\"36920787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic versus niche-mediated HSC effects not resolved\", \"Downstream transcriptional targets in HSCs unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Podocyte-specific MC5R reconstitution in MC5R⁻/⁻ mice, THSD7A nephropathy model, complement cascade analysis, cultured podocytes with PG-901\",\n      \"pmids\": [\"40739753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MC5R activates PPARγ is not defined\", \"Whether this complement-suppressive role extends to other glomerular diseases not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007165\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MC1R\",\n      \"PPARG\",\n      \"CFB\",\n      \"CFD\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}