Melanocortin 4 receptor

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in regulating energy homeostasis, appetite, and sexual function. It plays a key role in metabolic processes and is genetically linked to certain forms of obesity in humans.^[5][6][7] MC4R is a receptor that binds to α-melanocyte-stimulating hormone (α-MSH), influencing energy homeostasis and feeding behavior via the central nervous system. In [[mouse models]], MC4R has been shown to regulate feeding behavior, metabolism, reproductive function, and erectile response.^[8][9][10]

MC4R
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2IQP, 2IQR, 2IQS, 2IQU, 2IQV, 2IQW
Identifiers
Aliases	MC4R, Melanocortin 4 receptor, BMIQ20
External IDs	OMIM: 155541; MGI: 99457; HomoloGene: 4320; GeneCards: MC4R; OMA:MC4R - orthologs
Gene location (Human) Chr. Chromosome 18 (human)[1] Band 18q21.32 Start 60,371,062 bp[1] End 60,372,775 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18|18 E1 Start 66,990,775 bp[2] End 66,993,577 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube prefrontal cortex Hypothalamus caudate nucleus anterior cingulate cortex Brodmann area 9 putamen nucleus accumbens right frontal lobe Amygdala Top expressed in embryo embryo embryo thyroid gland dentate gyrus of hippocampal formation granule cell hippocampus proper neural tube primary visual cortex striatum of neuraxis Cortex of frontal lobe More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity peptide hormone binding melanocyte-stimulating hormone receptor activity protein binding melanocortin receptor activity ubiquitin protein ligase binding neuropeptide binding hormone binding Cellular component integral component of membrane membrane plasma membrane nucleus Biological process regulation of grooming behavior adenylate cyclase-modulating G protein-coupled receptor signaling pathway insulin secretion regulation of feeding behavior positive regulation of bone resorption diet induced thermogenesis response to insulin feeding behavior negative regulation of feeding behavior energy reserve metabolic process regulation of metabolic process signal transduction G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4160 17202 Ensembl ENSG00000166603 ENSMUSG00000047259 UniProt P32245 P56450 RefSeq (mRNA) NM_005912 NM_016977 RefSeq (protein) NP_005903 NP_058673 Location (UCSC) Chr 18: 60.37 – 60.37 Mb Chr 18: 66.99 – 66.99 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^{[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

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.

.mw-parser-output .template-chem2-su{display:inline-block;font-size:80%;line-height:1;vertical-align:-0.35em}.mw-parser-output .template-chem2-su>span{display:block;text-align:left}.mw-parser-output sub.template-chem2-sub{font-size:80%;vertical-align:-0.35em}.mw-parser-output sup.template-chem2-sup{font-size:80%;vertical-align:0.65em}Ca2+ 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 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

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

Paralogues

Source:^[34]

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

See also

• Melanocortin receptor