Melanocortin receptors: Introduction


The melanocortin system consists of five distinct receptors belonging to class A of seven-transmembrane G protein-coupled receptors (GPCRs), several agonists, and two endogenous inverse agonists, Agouti and Agouti-related peptide (AGRP) [4,41]. Melanocortin receptors are unique as they recognize both a family of peptide agonists encoded by the pro-opiomelanocortin (POMC) gene [27,39], and the inverse agonists, agouti and AGRP [13]. Melanocortin receptors have highly overlapping expression patterns as well as binding profiles in the brain and in the periphery [10,34] which is in line with the involvement of melanocortin peptides in numerous physiological functions such as energy homeostasis, pigmentation, sexual function, analgesia, inflammation, exocrine secretion, immunomodulation, and steroidogenesis [4,11,16,41,47-48]. The POMC gene is widely distributed and expressed both centrally and peripherally including skin [5,39]. POMC peptide is today known to be the precursor of 11 peptides (Pro-ACTH, β-LPH, N-POMC, JP, ACTH, α-MSH, β-MSH, γ-MSH, CLIP, γ-LPH, and β-Endorphin) several of which can be further biochemically modified into variants with distinct physiological functions [5,27,30,46]. The agouti gene is expressed primarily in follicular epithelial cells, and the AGRP gene is expressed in the arcuate nucleus of the hypothalamus and in the adrenal gland [45].

Five distinct receptors

There are five melanocortin receptors known at the present time, and each gene encodes a single protein version of each of the five receptors [34]. Almost 20 years after the sequencing of the POMC gene, the first melanocortin receptor gene, the MC1 receptor (MC1R), was sequenced [7-8,29] and the sequencing of MC2R [7,29], MC3R [17,33], MC4R [17-18,28] and MC5R [12,23,33,35,43] genes soon followed. Under NC-IUPHAR recommendations, the corresponding nomenclature would be MC1, MC2, MC3, MC4 and MC5.

The MC1 receptor (previously termed MSH-R) is expressed in melanocytes, keratinocytes, dermal fibroblasts, neutrophils, monocytes, B-lymphocytes, macrophages, endothelial cells, dendritic cells, glial cells, astrocytes and involved in the regulation of pigment production [42]. The MC2 receptor (originally termed ACTH-R) is expressed in the adrenal cortex, adipose tissue, bone cells, and involved in the regulation of glucocorticoid hormone production [29]. The MC3, MC4, and MC5 receptors had not been characterized as distinct pharmacological entities, but were cloned by homology to the MC1 and MC2 receptors [35]. They are distributed in both central and peripheral tissues and organs [5,10].

Functional characteristics

The physiology of the melanocortin receptors is simplified by the largely discrete distribution of the five receptors, and their functional roles are related to the responses mediated by the five known receptors [5,12,23]. The melanocortin system has a well-established role in the regulation of energy homeostasis [19,27,43], but there is growing evidence of its involvement in memory, nociception, mood disorders and addiction [5,12,32,34]. A common molecular link between the various physiological conditions in which melanocortins play a role is their involvement in synaptic plasticity [24,26,37]. Melanocortin signaling coordinates synaptic adaptations in response to physiological stimuli such as hormonal or nutrient signals [5].


Many of the well-characterized agonists and antagonists of the melanocortin receptors are peptides or proteins. The MC1 receptor, in most species, is effectively an α-MSH receptor. The MC2 receptor only recognizes the ACTH peptide. The MC3 receptor is unique in that, while it recognizes all of the melanocortin peptides, it is the only MC receptor that binds γ-MSH with high affinity. The MC4 receptor binds all of the melanocortin peptides, but only has high affinity for α-MSH and ACTH. The agouti peptide binds to the MC1 and MC4 receptors with high affinity in in vitro tests but, being normally expressed only in skin, only has access to the MC1 receptor under physiological conditions [25]. The AGRP peptide is a high-affinity antagonist of the neural MC3 receptor and the MC4 receptor [15,31,38].

Future directions

During the past two decades, melanocortin peptides and receptors have received considerable attention regarding several CNS functions besides the regulation of energy control, and the multiple roles of the melanocortins represent an opportunity for therapeutic interventions. Molecular tools have allowed the identification of melanocortin receptors signaling in memory, reward, mood and nociception, and erectile function [1-2,5,9,14,21,44], among others. Interestingly, a recent study investigated the effects of intranasally administered HS014, a selective MC4 receptor antagonist, and it resulted in marked resilience effects on the development of behavioral symptoms co-morbid with post-traumatic stress disorders [36]. Studies regarding the use of MC4 receptor agonists on weight loss resulted in transient decreases in food intake (35%) and persistent weight loss in a nonhuman primate model [22]. Similarly, the involvement of the melanocortins in regulation of behavioral and emotional states, neuroprotection, inflammation and exocrine secretion are likely to spur the discovery of selective MC1 and MC5 receptor compounds [3,6,16,20,40].


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1. Argiolas A, Melis MR. (2013) Neuropeptides and central control of sexual behaviour from the past to the present: a review. Prog Neurobiol, 108: 80-107. [PMID:23851261]

2. Bertolini A, Tacchi R, Vergoni AV. (2009) Brain effects of melanocortins. Pharmacol Res, 59 (1): 13-47. [PMID:18996199]

3. Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Lagu B, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I, Blackburn TP, Branchek TA, Gerald C, Vaysse PJ, Forray C. (2002) Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med, 8: 825-830. [PMID:12118247]

4. Carla Caruso, L. C., Daniela Durand, Teresa N. Scimonelli and Mercedes Lasaga. (2012) Melanocortins: Anti-Inflammatory and Neuroprotective Peptides. In Neurodegeneration Edited by L. Miguel Martins (InTech) .

5. Caruso V, Lagerström MC, Olszewski PK, Fredriksson R, Schiöth HB. (2014) Synaptic changes induced by melanocortin signalling. Nat Rev Neurosci, 15 (2): 98-110. [PMID:24588018]

6. Chaki S, Funakoshi T, Hirota-Okuno S, Nishiguchi M, Shimazaki T, Iijima M, Grottick AJ, Kanuma K, Omodera K, Sekiguchi Y, Okuyama S, Tran TA, Semple G, Thomsen W. (2005) Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists. J Pharmacol Exp Ther, 313: 831-839. [PMID:15677346]

7. Chhajlani V, Muceniece R, Wikberg JE. (1993) Molecular cloning of a novel human melanocortin receptor. Biochem Biophys Res Commun, 195 (2): 866-73. [PMID:8396929]

8. Chhajlani V, Wikberg JE. (1996) Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA (FEBS 11553). FEBS Lett, 390 (2): 238. [PMID:8706868]

9. Chu H, Xia J, Yang Z, Gao J. (2012) Melanocortin 4 receptor induces hyperalgesia and allodynia after chronic constriction injury by activation of p38 MAPK in DRG. Int J Neurosci, 122 (2): 74-81. [PMID:21985621]

10. Cone RD. (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci, 8 (5): 571-8. [PMID:15856065]

11. Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, Chen W, Orth DN, Pouton C, Kesterson RA. (1996) The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res, 51: 287-317; discussion 318. [PMID:8701084]

12. da Silva AA, do Carmo JM, Wang Z, Hall JE. (2014) The brain melanocortin system, sympathetic control, and obesity hypertension. Physiology (Bethesda), 29 (3): 196-202. [PMID:24789984]

13. Dinulescu DM, Cone RD. (2000) Agouti and agouti-related protein: analogies and contrasts. J Biol Chem, 275 (10): 6695-8. [PMID:10702221]

14. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature, 385 (6612): 165-8. [PMID:8990120]

15. Fong TM, Mao C, MacNeil T, Kalyani R, Smith T, Weinberg D, Tota MR, Van der Ploeg LH. (1997) ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Commun, 237 (3): 629-31. [PMID:9299416]

16. Gantz I, Fong TM. (2003) The melanocortin system. Am J Physiol Endocrinol Metab, 284 (3): E468-74. [PMID:12556347]

17. Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T. (1993) Molecular cloning of a novel melanocortin receptor. J Biol Chem, 268 (11): 8246-50. [PMID:8463333]

18. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ, DelValle J, Yamada T. (1993) Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem, 268 (20): 15174-9. [PMID:8392067]

19. Ghamari-Langroudi M, Digby GJ, Sebag JA, Millhauser GL, Palomino R, Matthews R, Gillyard T, Panaro BL, Tough IR, Cox HM et al.. (2015) G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature, 520 (7545): 94-8. [PMID:25600267]

20. Giuliani D, Mioni C, Altavilla D, Leone S, Bazzani C, Minutoli L, Bitto A, Cainazzo MM, Marini H, Zaffe D et al.. (2006) Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology, 147 (3): 1126-35. [PMID:16254026]

21. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD et al.. (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell, 88 (1): 131-41. [PMID:9019399]

22. Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, Pranger L, Cowley MA, Grove KL, Culler MD. (2013) Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes, 62 (2): 490-7. [PMID:23048186]

23. Koch M, Horvath TL. (2014) Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism. Mol Psychiatry, 19 (7): 752-61. [PMID:24732669]

24. Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. (2012) Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature, 487 (7406): 183-9. [PMID:22785313]

25. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO et al.. (1994) Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature, 371 (6500): 799-802. [PMID:7935841]

26. Mansour AR, Farmer MA, Baliki MN, Apkarian AV. (2014) Chronic pain: the role of learning and brain plasticity. Restor Neurol Neurosci, 32 (1): 129-39. [PMID:23603439]

27. Mountjoy KG. (2015) Pro-Opiomelanocortin (POMC) Neurones, POMC-Derived Peptides, Melanocortin Receptors and Obesity: How Understanding of this System has Changed Over the Last Decade. J Neuroendocrinol, 27 (6): 406-18. [PMID:25872650]

28. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. (1994) Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol, 8 (10): 1298-308. [PMID:7854347]

29. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. (1992) The cloning of a family of genes that encode the melanocortin receptors. Science, 257 (5074): 1248-51. [PMID:1325670]

30. Nakanishi S, Inoue A, Kita T, Nakamura M, Chang AC, Cohen SN, Numa S. (1979) Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature, 278 (5703): 423-7. [PMID:221818]

31. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science, 278 (5335): 135-8. [PMID:9311920]

32. Pandit R, van der Zwaal EM, Luijendijk MC, Brans MA, van Rozen AJ, Oude Ophuis RJ, Vanderschuren LJ, Adan RA, la Fleur SE. (2015) Central melanocortins regulate the motivation for sucrose reward. PLoS ONE, 10 (3): e0121768. [PMID:25811380]

33. Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RD. (1993) Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci USA, 90 (19): 8856-60. [PMID:8415620]

34. Schiöth HB. (2001) The physiological role of melanocortin receptors. Vitam Horm, 63: 195-232. [PMID:11358115]

35. Schiöth HB, Haitina T, Ling MK, Ringholm A, Fredriksson R, Cerdá-Reverter JM, Klovins J. (2005) Evolutionary conservation of the structural, pharmacological, and genomic characteristics of the melanocortin receptor subtypes. Peptides, 26 (10): 1886-900. [PMID:15985310]

36. Serova LI, Laukova M, Alaluf LG, Sabban EL. (2013) Intranasal infusion of melanocortin receptor four (MC4R) antagonist to rats ameliorates development of depression and anxiety related symptoms induced by single prolonged stress. Behav Brain Res, 250: 139-47. [PMID:23680165]

37. Shen Y, Fu WY, Cheng EY, Fu AK, Ip NY. (2013) Melanocortin-4 receptor regulates hippocampal synaptic plasticity through a protein kinase A-dependent mechanism. J Neurosci, 33 (2): 464-72. [PMID:23303927]

38. Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL. (1997) Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev, 11 (5): 593-602. [PMID:9119224]

39. Smith AI, Funder JW. (1988) Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues. Endocr Rev, 9: 159-179. [PMID:3286233]

40. Spaccapelo L, Bitto A, Galantucci M, Ottani A, Irrera N, Minutoli L, Altavilla D, Novellino E, Grieco P, Zaffe D et al.. (2011) Melanocortin MC₄ receptor agonists counteract late inflammatory and apoptotic responses and improve neuronal functionality after cerebral ischemia. Eur J Pharmacol, 670 (2-3): 479-86. [PMID:21946115]

41. Tao YX. (2010) The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev, 31 (4): 506-43. [PMID:20190196]

42. Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. (1995) Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet, 11 (3): 328-30. [PMID:7581459]

43. van der Klaauw A, Keogh J, Henning E, Stephenson C, Trowse VM, Fletcher P, Farooqi S. (2015) Role of melanocortin signalling in the preference for dietary macronutrients in human beings. Lancet, 385 Suppl 1: S12. [PMID:26312834]

44. Van der Ploeg LH, Martin WJ, Howard AD, Nargund RP, Austin CP, Guan X, Drisko J, Cashen D, Sebhat I, Patchett AA et al.. (2002) A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci USA, 99 (17): 11381-6. [PMID:12172010]

45. Västermark A, Schiöth HB. (2011) The early origin of melanocortin receptors, agouti-related peptide, agouti signalling peptide, and melanocortin receptor-accessory proteins, with emphasis on pufferfishes, elephant shark, lampreys, and amphioxus. Eur J Pharmacol, 660 (1): 61-9. [PMID:21208605]

46. Wardlaw SL. (2011) Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol, 660 (1): 213-9. [PMID:21208604]

47. Wikberg JE, Mutulis F. (2008) Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov, 7 (4): 307-23. [PMID:18323849]

48. Yang Y. (2011) Structure, function and regulation of the melanocortin receptors. Eur J Pharmacol, 660 (1): 125-30. [PMID:21208602]

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