Melanocortin receptors (MC1-5R) — Gs-coupled GPCRs activated by POMC-derived peptides (α-MSH, β-MSH, γ-MSH, ACTH). MC1R on melanocytes mediates eumelanin synthesis (skin pigmentation); MC2R is the ACTH receptor on adrenal cortex; MC3R + MC4R in hypothalamus regulate appetite + energy balance; MC5R has thermoregulation + exocrine roles. Therapeutic / research peptides: setmelanotide (Imcivree) — MC4R-selective agonist for monogenic obesity (POMC, PCSK1, LEPR deficiency, BBS); pt-141 (bremelanotide) — MC1R/MC3R/MC4R nonselective agonist for hypoactive sexual desire disorder (premenopausal women); melanotan-ii — MC1R-biased nonselective agonist marketed as tanning peptide (unregulated; melanoma risk + nausea + spontaneous erections). α-MSH is the canonical endogenous ligand.
Organ Systems
endocrine
integumentary
nervous
Pathway Steps
pomc → alpha-msh — via PC1/3 + PC2 prohormone convertase cleavage in hypothalamic arcuate nucleus + skin. Pro-opiomelanocortin (POMC) is a precursor cleaved by prohormone convertases into several peptides, including α-melanocyte-stimulating hormone (α-MSH) and ACTH. The same precursor serves pigmentation, adrenal, and appetite functions — and POMC mutations cause early-onset obesity with adrenal insufficiency and red hair.
alpha-msh → mc1r-melanogenesis — via MC1R on melanocytes → cAMP → MITF → tyrosinase → eumelanin. α-MSH acts on the melanocortin-1 receptor (MC1R) on melanocytes to stimulate eumelanin (brown/black pigment) synthesis. MC1R variants that weaken this signaling give red hair, fair skin, and poor tanning — raising melanoma risk; this is the receptor mimicked by tanning peptides like afamelanotide.
alpha-msh → mc4r-appetite-suppression — via MC4R on PVN neurons → reduced food intake. In the hypothalamus, α-MSH acts on the melanocortin-4 receptor (MC4R) to suppress appetite — the dominant central anorexigenic signal, opposed by AgRP. MC4R is the most common monogenic cause of obesity, and MC4R agonists (setmelanotide) treat specific genetic obesity syndromes.