Nomenclature: MC3 receptor

Family: Melanocortin receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 360 20q13.2 MC3R melanocortin 3 receptor 7,22
Mouse 7 323 2 H3 Mc3r melanocortin 3 receptor 6
Rat 7 323 3q42 Mc3r melanocortin 3 receptor 5,19
Previous and Unofficial Names
MC3R
γ-MSH receptor
MC3
MC3-R
melanocortin 3 receptor
melanocortin receptor 3
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligand(s)
ACTH {Sp: Mouse, Rat} , ACTH {Sp: Human}
α-MSH {Sp: Human, Mouse, Rat}
β-MSH {Sp: Human} , β-MSH {Sp: Mouse} , β-MSH {Sp: Rat}
γ-MSH {Sp: Human, Mouse, Rat}
Comments: γ-MSH is the principal endogenous agonist
Rank order of potency (Human)
γ-MSH (POMC, P01189), β-MSH (POMC, P01189) > ACTH (POMC, P01189), α-MSH (POMC, P01189)
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[125I]NDP-MSH Hs Full agonist 9.7 pKd 14
pKd 9.7 (Kd 2x10-10 M) [14]
γ-MSH {Sp: Human, Mouse, Rat} Hs Full agonist 8.5 pKd 18
pKd 8.5 [18]
NDP-MSH Hs Full agonist 8.9 pKi 1
pKi 8.9 [1]
MT-II Hs Full agonist 8.3 pKi 1
pKi 8.3 [1]
α-MSH {Sp: Human, Mouse, Rat} Hs Full agonist 8.0 – 8.4 pKi 1,18
pKi 8.0 – 8.4 [1,18]
[D-Trp8]γ-MSH Hs Full agonist 8.2 pIC50 8
pIC50 8.2 [8]
Agonist Comments
The MC3 is the only MC at which γ-MSH has high affinity.

Commonly used radioligands include [125I]NDP-MSH and [125I]AGRP(86-132).
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
HS024 Hs Antagonist 8.3 pKd 12
pKd 8.3 [12]
HS014 Hs Antagonist 7.3 pKd 21
pKd 7.3 [21]
SHU9119 Rn Antagonist 9.1 pKi 1
pKi 9.1 (Ki 8.79x10-10 M) [1]
SHU9119 Hs Antagonist 8.9 – 9.1 pKi 11,15,21
pKi 8.9 – 9.1 [11,15,21]
PG-901 Hs Antagonist 9.7 pIC50 10
pIC50 9.7 [10]
agouti-related protein {Sp: Human} Hs Inverse agonist 7.7 pIC50 20
pIC50 7.7 [20]
agouti {Sp: Mouse} Mm Inverse agonist 6.7 pIC50 13
pIC50 6.7 [13]
PG-106 Hs Antagonist 6.7 pIC50 9
pIC50 6.7 (IC50 2.1x10-7 M) [9]
View species-specific antagonist tables
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  7
Secondary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown) Other - See Comments
Comments:  Melanocortin activation of the MC3 mobilizes intracellular calcium via an incompletely understood pathway(s).
References:  16,23
Tissue Distribution
Stomach, duodenum and pancreas.
Species:  Human
Technique:  PCR and Southern Blotting.
References:  7
Heart.
Species:  Human
Technique:  PCR and hybridisation.
References:  4
Placenta.
Species:  Human
Technique:  Northern blotting.
References:  7
Brain: Cortex, thalamus, hippocampus, hypothalamus.
Species:  Mouse
Technique:  in situ hybridisation.
References:  7
Brain: Mainly found in the hypothalamus, but small amounts found in other brain regions.
Species:  Rat
Technique:  Northern Blotting and in situ hybridisation.
References:  19
Brain.
Species:  Rat
Technique:  Northern blotting.
References:  7
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of intracellular Ca+2 in HEK 293 cells transfected with the MC3 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Mobilisation of [Ca+2]i.
References:  16
Measurement of cAMP levels in cell lines transfected with the MC3 receptor.
Species:  Human
Tissue:  HEK 293 and COS cells.
Response measured:  Intracellular cAMP accumulation.
References:  7
Measurement of cAMP levels in cells transfected with the MC3 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Increase in cAMP.
References:  24
Measurement of cAMP levels in COS-1 cells transfected with the rat MC3 receptor.
Species:  Rat
Tissue:  COS-1 cells.
Response measured:  cAMP accumulation.
References:  5
Physiological Functions
Naturesis.
Species:  Mouse
Tissue:  In vivo.
References:  17
Energy homeostasis.
Species:  Mouse
Tissue:  In vivo
References:  2-3
Physiological Consequences of Altering Gene Expression
MC3 receptor knockouts exhibit a metabolic syndrome. At 4-6 months old, MC3 receptor knockout mice show increased fat mass, reduced lean mass and a higher feed efficiency, with normal metabolic rates. MC3 knockout mice are hyperleptinaemic and males are often mildly hyperinsulinaemic.
Species:  Human
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3
MC3 receptor knockouts exhibit a metabolic syndrome. MC3 receptors show a 50-60% increase in adipose mass, an increase in respiratory quotient when transferred to a high fat diet (suggesting a reduced ratio of fat/carbohydrate oxidation), and a 50% reduction in locomotor activity (reduced energy expenditure).
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  2
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0009116 abnormal brown fat cell morphology PMID: 10973258 
Mc3rtm1Cone Mc3rtm1Cone/Mc3rtm1Cone
involves: 129S4/SvJae * C57BL/6J
MGI:96929  MP:0005449 abnormal food intake PMID: 10965927 
Mc3rtm1Cone Mc3rtm1Cone/Mc3rtm1Cone
involves: 129S4/SvJae * C57BL/6J
MGI:96929  MP:0004129 abnormal respiratory quotient PMID: 10965927 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0003491 abnormal voluntary movement PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0001258 decreased body length PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0009128 decreased brown fat cell number PMID: 10973258 
Mc3rtm1Cone Mc3rtm1Cone/Mc3rtm1Cone
B6.129S4-Mc3r
MGI:96929  MP:0003910 decreased eating behavior PMID: 15034587 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0003910 decreased eating behavior PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0003961 decreased lean body mass PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0001402 hypoactivity PMID: 10973258 
Mc3rtm1Cone Mc3rtm1Cone/Mc3rtm1Cone
involves: 129S4/SvJae * C57BL/6J
MGI:96929  MP:0001260 increased body weight PMID: 10965927 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0001260 increased body weight PMID: 10973258 
Mc3rtm1Lvp|Mc4rtm1Dhu Mc3rtm1Lvp/Mc3rtm1Lvp,Mc4rtm1Dhu/Mc4rtm1Dhu
involves: 129S4/SvJae * 129S7/SvEvBrd * C57BL/6J
MGI:96929  MGI:99457  MP:0001260 increased body weight PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0002079 increased circulating insulin level PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0005669 increased circulating leptin level PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0005658 increased susceptibility to diet-induced obesity PMID: 10973258 
Mc3rtm1Cone Mc3rtm1Cone/Mc3rtm1Cone
involves: 129S4/SvJae * C57BL/6J
MGI:96929  MP:0010024 increased total body fat amount PMID: 10965927 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0010024 increased total body fat amount PMID: 10973258 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0009118 increased white fat cell size PMID: 10973258 
Mc3rtm1Cone Mc3rtm1Cone/Mc3rtm1Cone
involves: 129S4/SvJae * C57BL/6J
MGI:96929  MP:0001261 obese PMID: 10965927 
Mc3r+|Mc3rtm1Cone Mc3rtm1Cone/Mc3r+
involves: 129S4/SvJae * C57BL/6J
MGI:96929  MP:0001261 obese PMID: 10965927 
Mc3rtm1Lvp Mc3rtm1Lvp/Mc3rtm1Lvp
involves: 129S7/SvEvBrd * C57BL/6J
MGI:96929  MP:0003109 short femur PMID: 10973258 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Susceptibility to severe obesity
OMIM:  602025
Orphanet:  217031
References: 
Mutations not determined
Available Assays
DiscoveRx PathHunter® CHO-K1 MC3R β-Arrestin Cell Line (Cat no. 93-0502C2)
PathHunter® eXpress MC3R CHO-K1 β-Arrestin GPCR Assay (Cat no. 93-0502E2CP2M)
more info

REFERENCES

1. Adan RA, Szklarczyk AW, Oosterom J, Brakkee JH, Nijenhuis WA, Schaaper WM, Meloen RH, Gispen WH. (1999) Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat. Eur J Pharmacol378: 249-258. [PMID:10493100]

2. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M, Cone RD. (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology141: 3518-3521. [PMID:10965927]

3. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH. (2000) Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat. Genet.26: 97-102. [PMID:10973258]

4. Chhajlani V. (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int.38: 73-80. [PMID:8932521]

5. Daniels D, Suzuki A, Shapiro E, Luo L, Yee DK, Fluharty SJ. (2005) Rattus norvegicus melanocortin 3 receptor: A corrected sequence. Peptides26: 1835-1841. [PMID:15985309]

6. Desarnaud F, Labbe O, Eggerickx D, Vassart G, Parmentier M. (1994) Molecular cloning, functional expression and pharmacological characterization of a mouse melanocortin receptor gene. Biochem J.299: 367-373. [PMID:8172596]

7. Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T. (1993) Molecular cloning of a novel melanocortin receptor. J. Biol. Chem.268: 8246-8250. [PMID:8463333]

8. Grieco P, Balse PM, Weinberg D, MacNeil T, Hruby VJ. (2000) D-Amino acid scan of γ-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity. J. Med. Chem.43: 4998-5002. [PMID:11150170]

9. Grieco P, Cai M, Han G, Trivedi D, Campiglia P, Novellino E, Hruby VJ. (2007) Further structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5. Peptides28 (6): 1191-6. [PMID:17482720]

10. Grieco P, Lavecchia A, Cai M, Trivedi D, Weinberg D, MacNeil T, Van der Ploeg LH, Hruby VJ. (2002) Structure-activity studies of the melanocortin peptides: discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors. J. Med. Chem.45: 5287-5294. [PMID:12431055]

11. Hruby VJ, Lu D, Sharma SD, Castrucci AL, Kesterson RA, al-Obeidi FA, Hadley ME, Cone RD. (1995) Cyclic lactam α-melanotropin analogues of Ac-Nle4-c[Asp4,D-Phe7, Lys10] α-MSH(4-10)-NH2with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J. Med. Chem.38: 3454-3461. [PMID:7658432]

12. Kask A, Mutulis F, Muceniece R, Pähkla R, Mutule I, Wikberg JE, Rägo L, Schiöth HB. (1998) Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo. Endocrinology139: 5006-5014. [PMID:9832440]

13. Kiefer LL, Veal JM, Mountjoy KG, Wilkison WO. (1998) Melanocortin receptor binding determinants in the agouti protein. Biochemistry37 (4): 991-7. [PMID:9454589]

14. Kopanchuk S, Veiksina S, Petrovska R, Mutule I, Szardenings M, Rinken A, Wikberg JE. (2005) Co-operative regulation of ligand binding to melanocortin receptor subtypes: evidence for interacting binding sites. Eur J Pharmacol512: 85-95. [PMID:15840392]

15. MacNeil DJ, Howard AD, Guan X, Fong TM, Nargund RP, Bednarek MA, Goulet MT, Weinberg DH, Strack AM, Marsh DJ, Chen HY, Shen CP, Chen AS, Rosenblum CI, MacNeil T, Tota M, MacIntyre ED, Van der Ploeg LH. (2002) The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. Eur. J. Pharmacol.440: 141-157. [PMID:12007532]

16. Mountjoy KG, Kong PL, Taylor JA, Willard DH, Wilkison WO. (2001) Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells. . Physiol. Genomics5: 11-19. [PMID:11161002]

17. Ni XP, Pearce D, Butler AA, Cone RD, Humphreys MH. (2003) Genetic disruption of gamma-melanocyte-stimulating hormone signaling leads to salt-sensitive hypertension in the mouse. J. Clin. Invest.111: 1251-1258. [PMID:12697744]

18. Oosterom J, Nijenhuis WA, Schaaper WM, Slootstra J, Meloen RH, Gispen WH, Burbach JP, Adan RA. (1999) Conformation of the core sequence in melanocortin peptides directs selectivity for the melanocortin MC3 and MC4 receptors. J. Biol. Chem.274: 16853-16860. [PMID:10358030]

19. Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RD. (1993) Identification of a receptor forγ-MSH and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl. Acad. Sci. U.S.A.90: 8856-8860. [PMID:8415620]

20. Rosenfeld RD, Zeni L, Welcher AA, Narhi LO, Hale C, Marasco J, Delaney J, Gleason T, Philo JS, Katta V, Hui J, Baumgartner J, Graham M, Stark KL, Karbon W. (1998) Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein. Biochemistry37: 16041-16052. [PMID:9819197]

21. Schioth HB, Muceniece R, Mutulis F, Bouifrouri AA, Mutule I, Wikberg JE. (1999) Further pharmacological characterization of the selective melanocortin 4 receptor antagonist HS014: comparison with SHU9119. Neuropeptides33: 191-196. [PMID:10657491]

22. Schioth HB, Muceniece R, Wikberg JE, Szardenings M. (1996) Alternative translation initiation codon for the human melanocortin MC3 receptor does not affect the ligand binding. Eur. J. Pharmacol.314: 381-384. [PMID:8957262]

23. Wachira SJ, Hughes-Darden CA, Taylor CV, Ochillo R, Robinson TJ. (2003) Evidence for the interaction of protein kinase C and melanocortin 3-receptor signaling pathways. Neuropeptides37: 201-210. [PMID:12906838]

24. Yang Y-K Dickinson C, Lae Y-M, Li J-Y, Ira Gantz I. (2001) Functional properties of an agouti signaling protein variant and binding characteristics of its cognate radioligand. . Am. J. Physiol. Regul. Integr. Comp. Physiol.281: 1877-1886. [PMID:11705773]

To cite this database page, please use the following:

Tung Fong, Helgi Schiöth, Ira Gantz, Roger D. Cone, Sadaf Farooqi, Carrie Haskell-Luevano, Victor J. Hruby, Kathleen G. Mountjoy, Jeffrey B. Tatro, Jarl E. S. Wikberg.
Melanocortin receptors: MC3 receptor. Last modified on 26/08/2013. Accessed on 25/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=284.

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