MC4R

G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor. Functions as a central component of the leptin-melanocortin pathway, which is essential for maintaining energy homeostasis. Upon activation, couples to G(s) protein, stimulating adenylate cyclase and the cAMP-dependent signaling pathway, which promotes anorexogenic signaling in the hypothalamus and contributes to a negative energy balance. Regulates food intake: activation by agonists suppresses appetite, whereas the antagonist Agouti-related protein/AGRP precludes agonist-induced signaling, thereby stimulating appetite. Modulates the firing activity of neurons in paraventricular nucleus (PVN) of the hypothalamus via alpha-MSH and AGRP regulation of inwardly rectifying potassium channel KCNJ13 closure, independently of G(s) signaling. In the PVN, also interacts with opsin 3/OPN3, which couples to G(i/o) proteins to inhibit MC4R-mediated cAMP signaling, thereby promoting food intake. In intestinal epithelial cells, contributes to inhibition of hepatic glucose production via nesfatin-1/NUCB2, leading to increased cAMP levels and glucagon-like peptide 1 (GLP-1) secretion. Interaction with MGRN1 displaces the G(s) protein, further decreasing MC4R signaling activity. Also activated by gamma-MSH, though with low potency..

Function from UniProtKB (P32245), read 2026-09-23. CC BY 4.0.