Melanocortin 1, 3, 4, and 5 receptors (MC1R, MC3R, MC4R, MC5R)

The melanocortin 1, 3, 4, and 5 receptors are four of the five known melanocortin receptor family members, which are G protein–coupled receptors expressed in a tissue-specific manner and activated by melanocortin peptides (α-, β-, and γ-MSH, ACTH) derived from the proopiomelanocortin (POMC) precursor. MC1R is most abundant in melanocytes, regulating pigmentation, UV responses, and anti-inflammatory pathways. MC3R and MC4R are primarily expressed in the brain and peripheral tissues, where they regulate energy homeostasis, puberty, growth, food intake, and satiety; MC4R is a validated target for monogenic and syndromic human obesity. MC5R is distributed in multiple tissues, notably exocrine glands, and appears to regulate exocrine secretions, inflammatory processes, and immunomodulation, though its functions are less completely understood. Pharmacological efforts target these receptors for conditions including obesity (MC4R), pigmentation disorders (MC1R), sexual dysfunction (MC4R), and rare inflammatory or glandular diseases (MC1R, MC5R). Some drugs and endogenous ligands show limited subtype selectivity, contributing to overlapping physiological and side effect profiles.

Other names

MC1R: α-MSH receptorMC1R: melanocyte-stimulating hormone receptor 1MC3R: melanocortin receptor 3MC4R: melanocortin receptor 4MC5R: melanocortin receptor 5

Most drugs are agonists (activate the receptor, increasing cAMP and PKA signaling). Some antagonists/partial agonists (block or reduce receptor activity). Downstream pathways involve adenylyl cyclase activation, cAMP generation, and further intracellular signaling (including MAPK/JAK-STAT/potential CREB activation for anti-inflammatory effects, especially MC1R).