Melanocortin 4 receptor
Ensembl | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 18: 60.37 – 60.37 Mb | Chr 18: 66.99 – 66.99 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
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
In 2009, two very large
The MC4 receptor agonist
In 2008, MC4R mutations were reported to be associated with inherited human
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
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
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
Evolution
Paralogues[34]
- MC5R
- MC3R
- MC1R
- MC2R
- S1PR1
- LPAR1
- GPR12
- S1PR3
- LPAR2
- S1PR2
- GPR6
- GPR3
- LPAR3
- GPR119
- CNR1
- S1PR5
- S1PR4
- CNR2
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000166603 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047259 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 24047677.
- S2CID 21946787.
- ^ "Entrez Gene: MC4R melanocortin 4 receptor".
- S2CID 4304297.
- S2CID 14528879.
- PMID 12172010.
- S2CID 12331736.
- PMID 18454148.
- S2CID 764409.
- PMID 19079261.
- PMID 22566560.
- PMID 23920449.
- S2CID 22103245.
- PMID 24204009.
- S2CID 35953386.
- S2CID 233260097.
- PMID 32327598.
- ^ "Bremelanotide Acetate Monograph for Professionals". Drugs.com.
- S2CID 43121906.
- PMID 17584134.
- S2CID 22132459.
- S2CID 20727709.
- S2CID 25321970.
- PMID 17584135.
- PMID 25652247.
- PMID 18454148.
- PMID 17122358.
- PMID 11101306.
- PMID 9058374.
- ^ "GeneCards®: The Human Gene Database".
Further reading
- 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. 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. 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. 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. PMID 9392003.
- Yeo GS, 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. PMID 12045190.
External links
- "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.