Melanocortin 4 receptor
Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene.[5][6][7] 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.[8][9][10]
Clinical significance
[edit]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.[11][12][13][14] 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.[15] This finding was replicated again by another research group in the following year.[16] In accordance with the above, MC4 receptor agonists have garnered interest as potential treatments for obesity and insulin resistance,[17][18] while MC4 receptor antagonists have attracted interest as potential treatments for cachexia.[19] The structures of the receptor in complex with the agonist setmelanotide[20] and the antagonist SHU9119[21] 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.[22] Melanotan II, a synthetic analog of α-MSH, is marketed to the general population for sexual enhancement by internet retailers.[23] 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.[24] 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.[25][26] MC4 receptor antagonists produce pronounced antidepressant- and anxiolytic-like effects in animal models of depression and anxiety.[27][28] 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.[29]
In 2008, MC4R mutations were reported to be associated with inherited human obesity.[30] 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.[31]
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.[citation needed]
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).[citation needed] 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.[citation needed]
Interactions
[edit]The MC4 receptor has been shown to interact with proopiomelanocortin (POMC).[32][33] 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.
Ca2+ as a cofactor for ligand binding
[edit]GPCRs can bind a wide variety of extracellular ligands including physiological cations. Biological and pharmacological studies have previously implicated both Zn2+ and Ca2+ in the function of multiple members of the melanocortin receptor family. There is Ca2+ in the agonist-bound structure. The researches hypothesize that Ca2+ stabilizes the ligand-binding pocket and functions as an endogenous cofactor for the binding of α-MSH to MC4 receptor. Ca2+ is likely to bind when the receptor is exposed to extracellular Ca2+ concentrations (~1.2 mM in the extracellular space of the central nervous system) but might not be bound intracellularly (Ca2+ concentration: 100 nm), thus suggesting a potential regulatory role for Ca2+ in α-MSH–binding dynamics.
Signaling along the phospholipase C pathway can significantly raise the intracellular Ca2+ concentration, and this may constitute positive feedback from signaling of MC4 receptor or other receptors that result in Ca2+ 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
[edit]Agonists
[edit]Non-selective
[edit]- α-MSH
- β-MSH
- γ-MSH
- ACTH
- Afamelanotide
- Bremelanotide
- Melanotan II
- Modimelanotide
- Setmelanotide was approved by FDA as first-ever therapy for chronic weight management (IMCIVREE).The setmelanotide was advanced first-in-class, precision medicine that is designed to directly address the underlying cause of obesities driven by genetic deficits in the melanocortin-4 (MC4) receptor pathway.
Selective
[edit]- AZD2820
- LY-2112688
- MK-0493
- PF-00446687
- PG-931
- PL-6983
- Ro 27-3225 – also some activity at MC1
- THIQ
Antagonists
[edit]Non-selective
[edit]Selective
[edit]- HS-014
- HS-024
- JKC-363
- MCL-0020
- MCL-0042 – also a serotonin reuptake inhibitor
- MCL-0129
- ML-00253764
- MPB-10
Unknown
[edit]Evolution
[edit]- MC5R
- MC3R
- MC1R
- MC2R
- S1PR1
- LPAR1
- GPR12
- S1PR3
- LPAR2
- S1PR2
- GPR6
- GPR3
- LPAR3
- GPR119
- CNR1
- S1PR5
- S1PR4
- CNR2
See also
[edit]References
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047259 – Ensembl, May 2017
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- ^ Modi ME, Inoue K, Barrett CE, Kittelberger KA, Smith DG, Landgraf R, Young LJ (July 2015). "Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole". Neuropsychopharmacology. 40 (8): 1856–65. doi:10.1038/npp.2015.35. PMC 4839509. PMID 25652247.
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Further reading
[edit]- Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD (October 1994). "Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain". Molecular Endocrinology. 8 (10): 1298–308. doi:10.1210/mend.8.10.7854347. PMID 7854347. S2CID 32709901.
- Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ, et al. (July 1993). "Molecular cloning, expression, and gene localization of a fourth melanocortin receptor". The Journal of Biological Chemistry. 268 (20): 15174–9. doi:10.1016/S0021-9258(18)82452-8. PMID 8392067.
- Alvaro JD, Tatro JB, Quillan JM, Fogliano M, Eisenhard M, Lerner MR, et al. (September 1996). "Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction". Molecular Pharmacology. 50 (3): 583–91. PMID 8794897.
- Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I (March 1997). "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology. 11 (3): 274–80. doi:10.1210/mend.11.3.9898. PMID 9058374.
- Chagnon YC, Chen WJ, Pérusse L, Chagnon M, Nadeau A, Wilkison WO, Bouchard C (October 1997). "Linkage and association studies between the melanocortin receptors 4 and 5 genes and obesity-related phenotypes in the Québec Family Study". Molecular Medicine. 3 (10): 663–73. doi:10.1007/BF03401705. PMC 2230227. PMID 9392003.
- Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S (October 1998). "A frameshift mutation in MC4R associated with dominantly inherited human obesity". Nature Genetics. 20 (2): 111–2. doi:10.1038/2404. PMID 9771698. S2CID 7287831.
- Vaisse C, Clement K, Guy-Grand B, Froguel P (October 1998). "A frameshift mutation in human MC4R is associated with a dominant form of obesity". Nature Genetics. 20 (2): 113–4. doi:10.1038/2407. PMID 9771699. S2CID 40193066.
- Hinney A, Schmidt A, Nottebom K, Heibült O, Becker I, Ziegler A, et al. (April 1999). "Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans". The Journal of Clinical Endocrinology and Metabolism. 84 (4): 1483–6. doi:10.1210/jcem.84.4.5728. PMID 10199800.
- Yang YK, Dickinson CJ, Zeng Q, Li JY, Thompson DA, Gantz I (May 1999). "Contribution of melanocortin receptor exoloops to Agouti-related protein binding". The Journal of Biological Chemistry. 274 (20): 14100–6. doi:10.1074/jbc.274.20.14100. PMID 10318826.
- Ho G, MacKenzie RG (December 1999). "Functional characterization of mutations in melanocortin-4 receptor associated with human obesity". The Journal of Biological Chemistry. 274 (50): 35816–22. doi:10.1074/jbc.274.50.35816. PMID 10585465.
- Yang YK, Fong TM, Dickinson CJ, Mao C, Li JY, Tota MR, et al. (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry. 39 (48): 14900–11. doi:10.1021/bi001684q. PMID 11101306.
- Mergen M, Mergen H, Ozata M, Oner R, Oner C (July 2001). "A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity". The Journal of Clinical Endocrinology and Metabolism. 86 (7): 3448. doi:10.1210/jcem.86.7.7809. PMID 11443223.
- McNulty JC, Thompson DA, Bolin KA, Wilken J, Barsh GS, Millhauser GL (December 2001). "High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein". Biochemistry. 40 (51): 15520–7. CiteSeerX 10.1.1.522.4019. doi:10.1021/bi0117192. PMID 11747427.
- Brocke KS, Neu-Yilik G, Gehring NH, Hentze MW, Kulozik AE (February 2002). "The human intronless melanocortin 4-receptor gene is NMD insensitive". Human Molecular Genetics. 11 (3): 331–5. doi:10.1093/hmg/11.3.331. PMID 11823452.
- Yang Y, Chen M, Lai Y, Gantz I, Georgeson KE, Harmon CM (June 2002). "Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity". The Journal of Biological Chemistry. 277 (23): 20328–35. doi:10.1074/jbc.M201343200. PMID 11912210.
- Hansen MJ, Morris MJ (May 2002). "Evidence for an interaction between neuropeptide Y and the melanocortin-4 receptor on feeding in the rat". Neuropharmacology. 42 (6): 792–7. doi:10.1016/S0028-3908(02)00025-4. PMID 12015205. S2CID 29068487.
- Miraglia Del Giudice E, Cirillo G, Nigro V, Santoro N, D'Urso L, Raimondo P, et al. (May 2002). "Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity". International Journal of Obesity and Related Metabolic Disorders. 26 (5): 647–51. doi:10.1038/sj.ijo.0801983. PMID 12032748.
- Kim CS, Lee SH, Kim RY, Kim BJ, Li SZ, Lee IH, et al. (August 2002). "Identification of domains directing specificity of coupling to G-proteins for the melanocortin MC3 and MC4 receptors". The Journal of Biological Chemistry. 277 (35): 31310–7. doi:10.1074/jbc.M112085200. PMID 12045190.
External links
[edit]- "Melanocortin Receptors: MC4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-05.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.