Melanocortin 4 receptor

Melanocortin 4 receptor (MC₄R) is a melanocortin receptor that in humans is encoded by the gene. 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.

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. ''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.

MC₄ receptor agonists like bremelanotide (PT-141), PL-6983, and PF-00446687 are under investigation as powerful potential treatments for both female and male sexual dysfunction, including hypoactive sexual desire disorder and erectile dysfunction. Bremelanotide and melanotan II are already used for sexual enhancement by the general population via their accessibility due to online drug vendors. 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.

In 2008, ''MC4R'' mutations were reported to be associated with inherited human obesity. 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.

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). 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

* 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

See also

* Melanocortin receptor

References

Further reading

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External links

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{{Melanocortin receptor modulators

G protein-coupled receptors
Human proteins