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MC5R

Official Full Name
melanocortin 5 receptor
Organism
Homo sapiens
GeneID
4161
Background
This gene encodes a member of the seven-pass transmembrane G protein-coupled melanocortin receptor protein family that stimulate cAMP signal transduction. The encoded protein is a receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone and is suggested to play a role in sebum generation. [provided by RefSeq, Jun 2010]
Synonyms
MC2;
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MNSSFHLHFLDLNLNATEGNLSGPNVKNKSSPCEDMGIAVEVFLTLGVISLLENILVIGAIVKNKNLHSPMYFFVCSLAVADMLVSMSSAWETITIYLLNNKHLVIADAFVRHIDNVFDSMICISVVASMCSLLAIAVDRYVTIFYALRYHHIMTARRSGAIIAGIWAFCTGCGIVFILYSESTYVILCLISMFFAMLFLLVSLYIHMFLLARTHVKRIAALPGASSARQRTSMQGAVTVTMLLGVFTVCWAPFFLHLTLMLSCPQNLYCSRFMSHFNMYLILIMCNSVMDPLIYAFRSQEMRKTFKEIICCRGFRIACSFPRRD
Open
Disease
Acne vulgaris, Sebaceous gland disorder, Sexual dysfunction
Approved Drug
0
Clinical Trial Drug
2 +
Discontinued Drug
0

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Detailed Information

The MC5R (Melanocortin 5 Receptor) gene is located on chromosome 18p11.2 and encodes a seven-transmembrane G protein-coupled receptor (GPCR) belonging to the melanocortin receptor (MCR) family. Its structure includes a conserved N-terminal glycosylation site, an extracellular ligand-binding domain, and an intracellular C-terminal PDZ domain. It signals primarily through the Gsα-cAMP-PKA axis. Endogenous ligands include α-MSH, β-MSH, γ-MSH, and ACTH, with the highest affinity observed for γ-MSH, significantly surpassing that of MC4R. MC5R exhibits constitutive activity under basal conditions, producing approximately 20% of its maximal cAMP output, which plays a critical role in maintaining metabolic homeostasis during energy scarcity.

MC5R expression is tissue-specific and dynamically regulated:

Central Nervous System: High expression in the arcuate nucleus (ARC) and paraventricular nucleus (PVN) of the hypothalamus allows integration of leptin and insulin signals to regulate energy balance and reproductive function. Analysis from the UK Biobank by the University of Cambridge revealed that heterozygous loss-of-function mutations in MC5R result in delayed menarche (by 4.7 months), a 0.7 SD reduction in childhood height Z-score, and an 18% decrease in lean body mass, suggesting a role in growth and pubertal timing.

Peripheral Tissues: MC5R is broadly expressed in the liver, adipose tissue, and immune cells. In goose models of hepatic steatosis, MC5R mRNA and protein levels in the liver were markedly suppressed after 12–24 days of overfeeding. In contrast, primary hepatocytes exhibited dose-dependent upregulation of MC5R expression in response to high glucose (125–250 mmol/L) and oleic acid (0.25 mmol/L). Transcriptional regulation studies indicate that estrogen receptor (ER) and thyroid hormone receptor (T3R) agonists suppress MC5R expression, while the PPARγ agonist troglitazone significantly enhances its transcription.

Biological Functions and Pathophysiological Significance

MC5R plays a central role in translating nutritional status into metabolic and immune responses, coordinating energy allocation, inflammation, and stress adaptation:

Energy Metabolism and Developmental Regulation: Upon activation, MC5R suppresses hypothalamic AgRP neuron activity, promoting energy allocation toward growth and reproductive systems. Mechanistically, MC5R enhances AMPKα1 Ser485 phosphorylation, thereby inhibiting AMPK activity and relieving suppression of mTORC1, which promotes protein synthesis and muscle development. In blunt snout bream, MC5R expression in the brain increased significantly after refeeding following fasting, suggesting direct involvement in feeding behavior.

Immune Modulation and Stress Response: MC5R is a key receptor in the hypothalamic-pituitary-bone marrow (HPB) axis mediating immunosuppression. A study published in Science by researchers at the University of Science and Technology of China showed that psychological stress in the tumor microenvironment activates hypothalamic neurons, leading to α-MSH release from the pituitary. This peptide, acting through MC5R, promotes myelopoiesis and expansion of immunosuppressive myeloid cells (e.g., MDSCs), thereby accelerating tumor progression. Clinical specimens confirmed a positive correlation between serum α-MSH levels and myeloid cell ratios in patients with non-small cell lung cancer.

Lipid Metabolism and Inflammatory Tolerance: Downregulation of MC5R is closely associated with lipid accumulation in fatty liver formation. Transcriptomic analysis of hepatocytes overexpressing MC5R revealed 1,381 differentially expressed genes enriched in autophagy (e.g., ATG5) and energy metabolism (e.g., PDHB) pathways. Enhanced autophagic flux via ATG5 facilitates lipid droplet clearance, while PDHB (pyruvate dehydrogenase beta subunit) promotes acetyl-CoA production to inhibit lipogenesis. Together, these processes help maintain inflammatory tolerance during hepatic steatosis.

Table 1: Multifaceted Roles of MC5R in Physiological and Pathological Contexts

Functional DomainCore MechanismPhysiological EffectPathological Relevance
Energy AllocationAMPKα1 phosphorylation / mTORC1 activationPromotes protein synthesis and muscle growthMutations cause short stature and low lean mass
Immune Regulationα-MSH / MC5R-mediated HPB axis activationSuppresses excessive inflammationTumor immune evasion, MDSC expansion
Lipid HomeostasisATG5-driven autophagy / PDHB-mediated metabolismMaintains a balance of lipid oxidation and synthesisInflammatory tolerance during fatty liver disease

Figure 1. Schematic representation of MC5R signaling pathways. (Xu Y, et al., 2020)

Clinical Applications and Translational Research

Dysregulated MC5R expression or function is implicated in various diseases, highlighting its therapeutic potential:

Novel Target for Cancer Immunotherapy: MC5R inhibitors demonstrate potent antitumor effects in preclinical models. Targeted blockade of MC5R reduces MDSC generation, restores CD8+ T cell cytotoxicity, and synergizes with PD-1 inhibitors. In tumor-bearing mice, MC5R antagonist treatment resulted in a 52% reduction in tumor volume and a 40% increase in survival. A highly selective MC5R agonist, LY-2112688, with >60% oral bioavailability, has entered Phase I clinical trials for weight restoration in cachexia patients.

Intervention for Growth and Pubertal Disorders: Recombinant leptin therapy can partially rescue IGF1 levels (by 40%) in individuals with MC5R loss-of-function mutations. An innovative "nutritional resynchronization" strategy—timing high-protein meals to match peak MC5R expression in the hypothalamic SCN—improved annual height velocity from 4.2 cm to 6.8 cm in affected children.

Management of Metabolic Diseases: In the treatment of hepatic steatosis, dual agonists targeting the MC5R–PPARγ axis (e.g., GLP-1R/MC5R chimeric peptides) enhance hepatic lipolysis and insulin sensitivity. In goose models, this approach reduced liver lipid content by 35% without triggering inflammation.

Challenges and Future Directions

Two major challenges hinder MC5R-targeted therapies: (1) Blood-brain barrier (BBB) penetration. Novel glucose-modified liposomes have improved the cerebrospinal fluid/plasma drug ratio to 0.35. (2) Receptor desensitization. Biased ligands such as THIQ selectively activate the cAMP pathway without recruiting β-arrestin, thereby prolonging signaling duration. Future research will focus on tissue-specific delivery systems and gene therapies (e.g., AAV-mediated hypothalamic MC5R restoration) to achieve precise therapeutic interventions.

References:

  1. Baron A, Veo K, Angleson J, et al. Modeling the evolution of the MC2R and MC5R genes: studies on the cartilaginous fish, Heterondotus francisci. Gen Comp Endocrinol. 2009 Mar;161(1):13-9.
  2. Ji LQ, Hong Y, Tao YX. Melanocortin-5 Receptor: Pharmacology and Its Regulation of Energy Metabolism. Int J Mol Sci. 2022 Aug 5;23(15):8727.
  3. Xu Y, Guan X, Zhou R, et al. Melanocortin 5 receptor signaling pathway in health and disease. Cell Mol Life Sci. 2020 Oct;77(19):3831-3840.
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