Melanocortin 4 receptor explained

Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the gene.[1] [2] [3] It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.[4] [5] [6]

Clinical significance

In 2009, two very large genome-wide association studies of body mass index (BMI) confirmed the association of variants about 150 kilobases downstream of the MC4R gene with insulin resistance, obesity, and other anthropometric traits.[7] MC4R may also have clinical utility as a biomarker for predicting individual susceptibility to drug-induced adverse effects causing weight gain and related metabolic abnormalities. Another GWAS performed in 2012 identified twenty SNPs located ~190 Kb downstream of MC4R in association with severe antipsychotic-induced weight gain. This locus overlapped with the region previously identified in the 2009 studies. The rs489693 polymorphism, in particular, sustained a statistically robust signal across three replication cohorts and demonstrated consistent recessive effects.[8] This finding was replicated again by another research group in the following year.[9] In accordance with the above, MC4 receptor agonists have garnered interest as potential treatments for obesity and insulin resistance,[10] [11] while MC4 receptor antagonists have attracted interest as potential treatments for cachexia.[12] The structures of the receptor in complex with the agonist setmelanotide[13] and the antagonist SHU9119[14] have been determined.

The MC4 receptor agonist bremelanotide (PT-141), sold under the brand name Vyleesi, was approved in the United States as a treatment for low sexual desire in women in 2019.[15] Melanotan II, a synthetic analog of α-MSH, is marketed to the general population for sexual enhancement by internet retailers.[16] PL-6983 and PF-00446687 are under investigation as potential treatments for both female and male sexual dysfunction, including hypoactive sexual desire disorder and erectile dysfunction.[17] The non-selective melanocortin receptor agonist afamelanotide (NDP-α-MSH) has been found to induce brain-derived neurotrophic factor (BDNF) expression in the rodent brain via activation of the MC4 receptor and mediate "intense" neurogenesis and cognitive recovery in an animal model of Alzheimer's disease.[18] [19] MC4 receptor antagonists produce pronounced antidepressant- and anxiolytic-like effects in animal models of depression and anxiety.[20] [21] And agonists of the MC4 receptor such as melanotan II and PF-00446687, via activation of the central oxytocin system, have been found to promote pair bond formation in prairie voles and, due to these prosocial effects, have been suggested as possible treatments for social deficits in autism spectrum disorders and schizophrenia.[22]

In 2008, MC4R mutations were reported to be associated with inherited human obesity.[23] They were found in heterozygotes, suggesting an autosomal dominant inheritance pattern. However, based on other research and observations, these mutations seem to have an incomplete penetrance and some degree of codominance. It has a prevalence of 1.0–2.5% in people with body mass indices greater than 30, making it the most commonly known genetic defect predisposing people to obesity.[24]

In an exome-wide meta-analysis across three cohorts (UKB,GHS and MCPS), there were 16 genes for which there genetic variants was associated with BMI.

Among the 16 genes, the analysis identified two for which rare mutations are known to cause monogenic obesity: MC4R and PCSK1 (proprotein convertase subtilisin/kexin type 1). One study provides genetic evidence linking  rare coding variation to BMI and obesity-related phenotypes.

MC4R gene mutations are associated with early-onset severe obesity they effect of mutations on opacity in these two heterozygous coding genes among mutations in the MC4R gene (C293R and S94N) are:

• Rapid weight gains from early age (the most important feature).

• Development of severe obesity (BMI ≫97th percentile) at early ages, usually <3 years of age.

• Persistent food-seeking behavior, mostly reported from six months of age.

• Parental/siblings anthropometric data: suspect if relatives present normal anthropometric data.

• Tall stature/increased growth velocity (MC4R monogenic diabetes).There is limited treatment options for the most common form of monogenic obesity,  MC4R mutations symptoms can be treated with a Glucagon-like Peptide-1 Receptor Agonist liraglutide which cause weight loss by reducing appetite. They found that the effects of liraglutide 3.0 mg daily for 16 weeks causes weight reducing and glucose lowering and may be relevant treatment in the most common form of monogenic obesity.

Interactions

The MC4 receptor has been shown to interact with proopiomelanocortin (POMC).[25] [26] POMC is a precursor peptide pro-hormone which is cleaved into several other peptide hormones. All of the endogenous ligands of MC4 are produced by cleaving this one precursor peptide. These endogenous agonists include α-MSH, β-MSH, γ-MSH, and ACTH.

as a cofactor for ligand binding

GPCRs can bind a wide variety of extracellular ligands including physiological cations. Biological and pharmacological studies have previously implicated both and in the function of multiple members of the melanocortin receptor family. There is in the agonist-bound structure. The researches hypothesize that stabilizes the ligand-binding pocket and functions as an endogenous cofactor for the binding of α-MSH to MC4 receptor. is likely to bind when the receptor is exposed to extracellular concentrations (~1.2 mM in the extracellular space of the central nervous system) but might not be bound intracellularly (concentration: 100 nm), thus suggesting a potential regulatory role for in α-MSH–binding dynamics.

Signaling along the phospholipase C pathway can significantly raise the intracellular concentration, and this may constitute positive feedback from signaling of MC4 receptor or other receptors that result in flux. This discovery highlights the plasticity and multipronged regulation and control of this receptor and will aid in next-generation structure-based drug design of therapeutics for MC4R-related obesity.

Ligands

Agonists

Non-selective

Selective

Antagonists

Non-selective

Selective

Unknown

Evolution

Paralogues[27]

See also

Further reading

External links

Notes and References

  1. Magenis RE, Smith L, Nadeau JH, Johnson KR, Mountjoy KG, Cone RD . Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human . Mammalian Genome . 5 . 8 . 503–8 . August 1994 . 7949735 . 10.1007/BF00369320 . 24047677 .
  2. Sundaramurthy D, Campbell DA, Leek JP, Markham AF, Pieri LF . Assignment of the melanocortin 4 receptor (MC4R) gene to human chromosome band 18q22 by in situ hybridisation and radiation hybrid mapping . Cytogenetics and Cell Genetics . 82 . 1–2 . 97–8 . November 1998 . 9763669 . 10.1159/000015074 . 21946787 .
  3. Web site: Entrez Gene: MC4R melanocortin 4 receptor.
  4. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD . Role of melanocortinergic neurons in feeding and the agouti obesity syndrome . Nature . 385 . 6612 . 165–8 . January 1997 . 8990120 . 10.1038/385165a0 . 4304297 . 1997Natur.385..165F .
  5. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F . 6 . Targeted disruption of the melanocortin-4 receptor results in obesity in mice . Cell . 88 . 1 . 131–41 . January 1997 . 9019399 . 10.1016/S0092-8674(00)81865-6 . 14528879 . free .
  6. Van der Ploeg LH, Martin WJ, Howard AD, Nargund RP, Austin CP, Guan X, Drisko J, Cashen D, Sebhat I, Patchett AA, Figueroa DJ, DiLella AG, Connolly BM, Weinberg DH, Tan CP, Palyha OC, Pong SS, MacNeil T, Rosenblum C, Vongs A, Tang R, Yu H, Sailer AW, Fong TM, Huang C, Tota MR, Chang RS, Stearns R, Tamvakopoulos C, Christ G, Drazen DL, Spar BD, Nelson RJ, MacIntyre DE . 6 . A role for the melanocortin 4 receptor in sexual function . Proceedings of the National Academy of Sciences of the United States of America . 99 . 17 . 11381–6 . August 2002 . 12172010 . 123265 . 10.1073/pnas.172378699 . 2002PNAS...9911381V . free .
  7. Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, Froguel P, Balding D, Scott J, Kooner JS . 6 . Common genetic variation near MC4R is associated with waist circumference and insulin resistance . Nature Genetics . 40 . 6 . 716–8 . June 2008 . 18454146 . 10.1038/ng.156 . 12331736 .
  8. Malhotra AK, Correll CU, Chowdhury NI, Müller DJ, Gregersen PK, Lee AT, Tiwari AK, Kane JM, Fleischhacker WW, Kahn RS, Ophoff RA, Meltzer HY, Lencz T, Kennedy JL . 6 . Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain . Archives of General Psychiatry . 69 . 9 . 904–12 . September 2012 . 22566560 . 4166499 . 10.1001/archgenpsychiatry.2012.191 .
  9. Czerwensky F, Leucht S, Steimer W . MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain? . The International Journal of Neuropsychopharmacology . 16 . 9 . 2103–9 . October 2013 . 23920449 . 10.1017/S1461145713000849 . free .
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  12. Foster AC, Chen C . Melanocortin-4 receptor antagonists as potential therapeutics in the treatment of cachexia . Current Topics in Medicinal Chemistry . 7 . 11 . 1131–6 . 2007 . 17584133 . 10.2174/156802607780906663 . 35953386 .
  13. Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M . 6 . Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling . Science . 372 . 6544 . 808–814 . May 2021 . 33858992 . 10.1126/science.abf7958 . 2021Sci...372..808I . 233260097 .
  14. Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH, Han GW, McClary K, Mittal SR, Burdsall K, Stauch B, Wu L, Stevens SN, Peisley A, Williams SY, Chen V, Millhauser GL, Zhao S, Cone RD, Stevens RC . 6 . Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding . Science . 368 . 6489 . 428–433 . April 2020 . 32327598 . 7567314 . 10.1126/science.aaz8995 . 2020Sci...368..428Y .
  15. Web site: Bremelanotide Acetate Monograph for Professionals . Drugs.com.
  16. Evans-Brown M, Dawson RT, Chandler M, McVeigh J . Use of melanotan I and II in the general population . BMJ . 338 . b566 . February 2009 . 19224885 . 10.1136/bmj.b566 . 43121906 .
  17. Shadiack AM, Sharma SD, Earle DC, Spana C, Hallam TJ . Melanocortins in the treatment of male and female sexual dysfunction . Current Topics in Medicinal Chemistry . 7 . 11 . 1137–44 . 2007 . 17584134 . 10.2174/156802607780906681 .
  18. Giuliani D, Neri L, Canalini F, Calevro A, Ottani A, Vandini E, Sena P, Zaffe D, Guarini S . 6 . NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors . Molecular and Cellular Neurosciences . 67 . 13–21 . July 2015 . 26003413 . 10.1016/j.mcn.2015.05.004 . 11380/1067772 . 22132459 . free .
  19. Ramírez D, Saba J, Carniglia L, Durand D, Lasaga M, Caruso C . Melanocortin 4 receptor activates ERK-cFos pathway to increase brain-derived neurotrophic factor expression in rat astrocytes and hypothalamus . Molecular and Cellular Endocrinology . 411 . 28–37 . August 2015 . 25892444 . 10.1016/j.mce.2015.04.008 . 20727709 . 11336/15275 . free .
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  22. Modi ME, Inoue K, Barrett CE, Kittelberger KA, Smith DG, Landgraf R, Young LJ . Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole . Neuropsychopharmacology . 40 . 8 . 1856–65 . July 2015 . 25652247 . 4839509 . 10.1038/npp.2015.35 .
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  27. Web site: GeneCards®: The Human Gene Database .

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