Melanocortin System

The melanocortin system is built from a single gene product. Proopiomelanocortin is cut by prohormone convertases into ACTH, the alpha, beta and gamma forms of MSH, and beta-endorphin, with the tissue deciding which fragments appear: corticotrophs stop at ACTH, while arcuate neurons and skin process further to alpha-MSH. All five receptors, MC1R through MC5R, are Gs-coupled. MC1R governs pigmentation, MC2R is the ACTH receptor on the adrenal cortex, MC3R and MC4R are central, and MC5R sits on exocrine glands.

The system is unusual in having endogenous antagonists. Agouti signalling protein opposes alpha-MSH at MC1R, and agouti-related peptide, co-released with NPY from arcuate AgRP neurons, opposes it at MC3R and MC4R, so appetite is set by the balance between two opposing peptide populations rather than by one hormone's concentration. Approved drugs exist at both ends: afamelanotide, an MC1R agonist licensed in 2019 for erythropoietic protoporphyria, and setmelanotide for MC4R-pathway obesity.

Reading the family as one system explains most of its pharmacology. Because the receptors share a core His-Phe-Arg-Trp pharmacophore, selectivity is hard to engineer and a compound designed for one receptor usually retains activity at others. That is why melanocortin agonists arrive with a predictable cluster of effects - pigment change, nausea, blood pressure - whichever receptor was the intended target.

The commercial misreading runs the other way, treating shared chemistry as shared benefit. A tanning peptide's MC1R activity says nothing about its metabolic effects, and marketing that invokes POMC biology to imply hormonal upside is trading on a family resemblance. The genuine clinical overlap is narrower: an ACTH-secreting tumour can present with hyperpigmentation, because the fragments come from one precursor.