Melanocortin 3 receptor (MC3R) and Melanocortin 4 receptor (MC4R) (MC3R/MC4R)

The Melanocortin 3 receptor (MC3R) and Melanocortin 4 receptor (MC4R) are G protein-coupled receptors (GPCRs) that serve as critical mediators in the melanocortin signaling pathway, primarily located in the hypothalamus (UniProt P41968, P32245). These receptors are essential for the regulation of energy homeostasis, appetite, and body weight, responding to agonists like alpha-melanocyte-stimulating hormone (α-MSH) and antagonists like Agouti-related protein (AgRP) (PubMed PMID: 31504478). MC4R is a well-established target for treating obesity, as its activation promotes satiety and increases metabolic rate, while MC3R acts as a metabolic rheostat that regulates the efficiency of energy utilization (PubMed PMID: 34407401). Mutations in the MC4R gene are the most common cause of monogenic obesity in humans, making it a high-priority therapeutic target (PubMed PMID: 29405785). Drugs such as Setmelanotide have been approved for chronic weight management in patients with specific genetic deficiencies affecting this pathway, while Bremelanotide targets these receptors to treat female sexual interest/arousal disorder (FDA Label: Imcivree, Vyleesi). Clinical challenges in targeting these receptors include managing side effects like skin hyperpigmentation, which occurs due to cross-reactivity with the MC1 receptor, and potential cardiovascular effects such as increased blood pressure (PubMed PMID: 21103329).

Other names

MC3-RMC4-RMelanocortin receptor 3Melanocortin receptor 4MC3RMC4RMelanocortin 3 receptorMelanocortin 4 receptor

Agonism of MC3R and MC4R stimulates the Gs-protein/adenylyl cyclase pathway, leading to increased intracellular cAMP and subsequent activation of pathways that suppress appetite and increase energy expenditure.