Recombinant Human Melanocortin receptor 4 (MC4R) Protein

Function

G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor (PubMed:12646665, PubMed:14764818, PubMed:25163632, PubMed:32327598, PubMed:33858992, PubMed:8392067). Functions as a central component of the leptin-melanocortin pathway, which is essential for maintaining energy homeostasis (PubMed:32327598, PubMed:33858992). 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 (PubMed:12588803, PubMed:14764818, PubMed:25163632, PubMed:33858992). Regulates food intake: activation by agonists suppresses appetite, whereas the antagonist Agouti-related protein/AGRP precludes agonist-induced signaling, thereby stimulating appetite (PubMed:9311920, PubMed:29311635). 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 (PubMed:32327598). 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 (PubMed:39951488). 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 (PubMed:39562740). Interaction with MGRN1 displaces the G(s) protein, further decreasing MC4R signaling activity (PubMed:19737927). Also activated by gamma-MSH, though with low potency (PubMed:8392067)

Subcellular Location

Cell membrane (Multi-pass membrane protein); Cell projection, cilium membrane (Multi-pass membrane protein)

Disease Association

Obesity (OBESITY) : A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. [Disease susceptibility is associated with variants affecting the gene represented in this entry. Obesity due to MC4R deficiency is associated with reduced total cholesterol, low-density lipoprotein-cholesterol, triglycerides and hypertension, and relative protection from cardiovascular disease]

Tissue Specificity

Brain, placental, and gut tissues

Subunit

Homodimer; disulfide-linked, also forms higher order oligomers. Interacts with GNAS (PubMed:33858992). Interacts with ATRNL1 (By similarity). Interacts with MGRN1; this interaction competes with GNAS-binding and thus inhibits agonist-induced cAMP production. Interacts with MRAP and MRAP2; these associated factors increase ligand-sensitivity and generation of cAMP. Forms a complex with OPN3 and KCNJ13; interaction with OPN3 inhibits MC4R-mediated signaling (PubMed:39951488)

• Gantz I. et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. — J. Biol. Chem. (1993)
• Mountjoy K.G. et al. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. — Mol. Endocrinol. (1994)
• Kopatz S.A. et al. cDNA clones of human proteins involved in signal transduction sequenced by the Guthrie cDNA resource center (www.cdna.org). (JAN-)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Mural R.J. et al. PubMed: CI-5GBDQ6B103N1E (JUL-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Ollmann M.M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. — Science (1997)
• Chan L.F. et al. MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. — Proc. Natl. Acad. Sci. U.S.A. (2009)