Melanocortin 1 receptor (MC1 receptor) (MC1R)

The Melanocortin 1 receptor (MC1 receptor or MC1R) is a G protein-coupled receptor primarily expressed on melanocytes and overexpressed on melanoma cells, where it binds alpha-melanocyte-stimulating hormone (alpha-MSH) to drive eumelanin production via the cAMP/PKA pathway, protecting against UV-induced damage and oxidative stress. Activation also engages ERK and PI3K/AKT pathways, promoting DNA repair, anti-inflammatory effects, and cytotoxicity in CD8+ T cells, while polymorphisms in MC1R increase skin cancer risk by favoring pheomelanin synthesis. In disease, MC1R plays a dual role in melanoma, serving as a target for radiolabeled alpha-MSH peptide analogs (e.g., 64Cu-DOTA-NAPamide, 99mTc-CCMSH) that enable PET imaging and targeted radionuclide therapy with high tumor uptake and specificity in preclinical models. Its involvement in anti-inflammatory responses extends to neuroprotection and peripheral tissue protection, and links to obesity via melanocortin pathways make it a candidate for metabolic therapies. Therapeutic challenges include ensuring high specific activity for low-receptor-density tumors and selectivity to avoid side effects from related receptors like MC4R.

Other names

alpha-melanocyte-stimulating hormone receptorMelanocortin-1 receptorMC1 receptor

Agonism leading to cAMP/PKA pathway activation for eumelanogenesis and anti-oxidative protection; ERK, PI3K/AKT pathway activation; G-protein coupled receptor signaling for pigmentation, anti-inflammation, and melanoma targeting with radiolabeled peptides; Antagonism blocking receptor function