What is Melanocortin receptor?
Also called: MC1R, MC2R, MC3R, MC4R, MC5R, MCR
Any of five class A G protein-coupled receptors (MC1R–MC5R) activated by ACTH and the melanocyte-stimulating hormones; studied with ligands such as melanotan II and PT-141.
By the APL Research Team · Updated
Melanocortin receptors are the five G protein-coupled receptors, MC1R to MC5R, that respond to peptides cut from the precursor pro-opiomelanocortin (POMC): the melanocyte-stimulating hormones (α-, β- and γ-MSH) and adrenocorticotropic hormone (ACTH). Together with those agonists and two endogenous antagonists, agouti and agouti-related protein, they make up the melanocortin system, which has been linked to pigmentation, adrenal steroid production, energy homeostasis, natriuresis, erectile responses and exocrine secretion [1]. The first MSH and ACTH receptors were cloned in 1992 and defined a new GPCR subfamily [2]; all five are class A receptors that signal mainly through Gαs and cAMP.
The five receptors
| Receptor | Main location | Agonist recognition | Research context |
|---|---|---|---|
| MC1R | Melanocytes | α-MSH, ACTH and synthetic α-MSH analogues [3] | Pigmentation |
| MC2R | Adrenal cortex | ACTH only [3]; needs the accessory protein MRAP to reach the cell surface [4] | Glucocorticoid production |
| MC3R | Brain [3] | α-MSH family, ACTH; blocked by agouti-related protein [6] | Energy homeostasis |
| MC4R | Brain [3] | α-MSH family, ACTH; blocked by agouti-related protein [6] | Knockout mice develop obesity with overeating [5] |
| MC5R | Peripheral tissues [3] | α-MSH family, ACTH | Exocrine gland secretion |
Agouti-related protein is expressed in the hypothalamus and selectively antagonises MC3R and MC4R [6]; together with the MC4R-knockout phenotype [5], this put those two receptors at the centre of the energy-balance literature.
The pharmacophore and its analogues
α-MSH is a 13-residue peptide, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 [7]. Analogue work kept the central His-Phe-Arg-Trp segment and changed what surrounds it:
| Ligand | Structure | Reported pharmacology |
|---|---|---|
| NDP-MSH | [Nle4, D-Phe7]-α-MSH | 26 times as potent as α-MSH at stimulating melanoma adenylate cyclase; resistant to serum enzymes [8] |
| Melanotan II | Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2, a 23-membered lactam ring | About 90 times α-MSH potency in lizard skin assays, with prolonged activity [7]; recognised by MC1R, MC3R, MC4R and MC5R [3] |
| PT-141 (bremelanotide) | The same cyclic heptapeptide with a free C-terminal acid | One mass unit heavier than melanotan II (1025.2 vs 1024.2 g/mol) |
| D-Nal(2′)7 analogue (SHU9119) | Melanotan II with D-2′-naphthylalanine in place of D-Phe | Antagonist at MC4R (pA2 9.3) and MC3R (pA2 8.3) but full agonist at MC1R and MC5R [3] |
Points of confusion
- Not one receptor. Melanotan II and PT-141 are not MC4R-selective. Attributing an effect to a single subtype needs selective antagonists, knockout models or single-receptor cell lines [3].
- One residue can flip efficacy. Replacing D-Phe with a bulkier aromatic residue at the same position turned a pan-agonist into a mixed agonist/antagonist [3]; see receptor agonist for the terms.
- Early potency data are not mammalian. The cyclic analogue figures came from frog and lizard skin bioassays, which measure non-mammalian melanocyte receptors [7]; cloned human receptors behave differently.
- Amide versus acid matters for identity. The C-terminal change between melanotan II and PT-141 adds 0.98 Da (monoisotopic 1023.54 vs 1024.52 Da), the same shift as deamidation, so the isotope pattern needs careful reading in mass spectrometry; it also changes the molecular weight used in concentration maths. The sequence notation guide explains the "-NH2" and "-OH" suffixes.
References
- 1.Cone RD. Studies on the physiological functions of the melanocortin system. Endocr Rev. 2006. PubMed 17077189
- 2.Mountjoy KG, Robbins LS, Mortrud MT, et al. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992. PubMed 1325670
- 3.Hruby VJ, Lu D, Sharma SD, et al. Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem. 1995. PubMed 7658432
- 4.Metherell LA, Chapple JP, Cooray S, et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005. PubMed 15654338
- 5.Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997. PubMed 9019399
- 6.Ollmann MM, Wilson BD, Yang YK, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997. PubMed 9311920
- 7.Al-Obeidi F, Castrucci AM, Hadley ME, et al. Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J Med Chem. 1989. PubMed 2555512
- 8.Sawyer TK, Sanfilippo PJ, Hruby VJ, et al. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A. 1980. PubMed 6777774