Melanocortin 4 receptor

Clinical significance

The importance of the MC4R in the regulation of human body weight first became apparent in 1998 with the reports from two groups of single families in whom heterozygous frameshift mutations in MC4R cosegregated with dominantly inherited severe early-onset obesity.

In 2009, two very large genome-wide association studies of body mass index (BMI) confirmed the association of common variants about 150 kilobases downstream of the MC4R gene with insulin resistance, obesity, and other anthropometric traits. 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. This finding was replicated again by another research group in the following year. In accordance with the above, MC4 receptor agonists have garnered interest as potential treatments for obesity and insulin resistance, while MC4 receptor antagonists have attracted interest as potential treatments for cachexia. The structures of the receptor in complex with the agonist setmelanotide and the antagonist SHU9119 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. Melanotan II, a synthetic analog of α-MSH, is marketed to the general population for sexual enhancement by internet retailers. 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. 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. MC4 receptor antagonists produce pronounced antidepressant- and anxiolytic-like effects in animal models of depression and anxiety. 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.

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.

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. The effect of two exemplary heterozygous coding variants 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

• 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 be activated by peptide hormones encoded by proopiomelanocortin (POMC). 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.

{{chem2|Ca(2+)}} 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

• 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

• AZD2820
• LY-2112688
• MK-0493
• PF-00446687
• PG-931
• PL-6983
• Ro 27-3225 – also some activity at MC1
• THIQ

Antagonists

Non-selective

• Agouti-related peptide
• Agouti signalling peptide
• SHU-8914
• SHU-9005
• SHU-9119

Selective

• HS-014
• HS-024
• JKC-363
• MCL-0020
• MCL-0042 – also a serotonin reuptake inhibitor
• MCL-0129
• ML-00253764
• MPB-10

Unknown

• Semax

Evolution

[[Sequence homology|Paralogues]]

Source:

• MC5R
• MC3R
• MC1R
• MC2R
• S1PR1
• LPAR1
• GPR12
• S1PR3
• LPAR2
• S1PR2
• GPR6
• GPR3
• LPAR3
• GPR119
• CNR1
• S1PR5
• S1PR4
• CNR2

References

References

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2. (November 1998). "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.
3. "Entrez Gene: MC4R melanocortin 4 receptor".
4. (January 1997). "Role of melanocortinergic neurons in feeding and the agouti obesity syndrome". Nature.
5. (January 1997). "Targeted disruption of the melanocortin-4 receptor results in obesity in mice". Cell.
6. (August 2002). "A role for the melanocortin 4 receptor in sexual function". Proceedings of the National Academy of Sciences of the United States of America.
7. (October 1998). "A frameshift mutation in MC4R associated with dominantly inherited human obesity". Nature Genetics.
8. (October 1998). "A frameshift mutation in human MC4R is associated with a dominant form of obesity". Nature Genetics.
9. (June 2008). "Common genetic variation near MC4R is associated with waist circumference and insulin resistance". Nature Genetics.
10. (September 2012). "Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain". Archives of General Psychiatry.
11. (October 2013). "MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain?". The International Journal of Neuropsychopharmacology.
12. (April 2008). "Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction". Nature Reviews. Drug Discovery.
13. (February 2014). "Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity". The Journal of Endocrinology.
14. (2007). "Melanocortin-4 receptor antagonists as potential therapeutics in the treatment of cachexia". Current Topics in Medicinal Chemistry.
15. (May 2021). "Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling". Science.
16. (April 2020). "Determination of the melanocortin-4 receptor structure identifies Ca²⁺ as a cofactor for ligand binding". Science.
17. "Bremelanotide Acetate Monograph for Professionals".
18. (February 2009). "Use of melanotan I and II in the general population". BMJ.
19. (2007). "Melanocortins in the treatment of male and female sexual dysfunction". Current Topics in Medicinal Chemistry.
20. (July 2015). "NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors". Molecular and Cellular Neurosciences.
21. (August 2015). "Melanocortin 4 receptor activates ERK-cFos pathway to increase brain-derived neurotrophic factor expression in rat astrocytes and hypothalamus". Molecular and Cellular Endocrinology.
22. (August 2013). "Intranasal infusion of melanocortin receptor four (MC4R) antagonist to rats ameliorates development of depression and anxiety related symptoms induced by single prolonged stress". Behavioural Brain Research.
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24. (July 2015). "Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole". Neuropsychopharmacology.
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27. (March 1997). "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology.
28. "GeneCards®: The Human Gene Database".
29. (June 2008). "Common variants near MC4R are associated with fat mass, weight and risk of obesity". Nature Genetics.
30. (January 2009). "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity". Nature Genetics.
31. (January 2009). "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation". Nature Genetics.