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MC3 receptor

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Target not currently curated in GtoImmuPdb

Target id: 284

Nomenclature: MC3 receptor

Family: Melanocortin receptors

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 323 20q13.2 MC3R melanocortin 3 receptor 9,28
Mouse 7 323 2 94.8 cM Mc3r melanocortin 3 receptor 8
Rat 7 323 3q42 Mc3r melanocortin 3 receptor 7,24
Previous and Unofficial Names Click here for help
γ-MSH receptor | melanocortin receptor 3
Database Links Click here for help
Specialist databases
GPCRdb mc3r_mouse (Mm), mc3r_rat (Rn)
Other databases
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins Click here for help
Interacting Proteins
Name Effect References
melanocortin-2 receptor accessory protein 2 (MRAP2) Essential for receptor activity and sensitivity to ligands 18
Natural/Endogenous Ligands Click here for help
ACTH {Sp: Human} , ACTH {Sp: Mouse, Rat}
agouti {Sp: Mouse}
agouti-related protein {Sp: Human}
β-MSH {Sp: Human}
α-MSH {Sp: Human, Mouse, Rat}
γ-MSH {Sp: Human, Mouse, Rat}
β-MSH {Sp: Mouse} , β-MSH {Sp: Rat}
Comments: γ-MSH is the principal endogenous agonist. Endogenous antagonists are agouti and agouti-related protein. For representations of the rodent orthologues of these peptides see agouti (mouse), agouti (rat) and agouti-related protein (mouse).
Potency order of endogenous agonists (Human)
γ-MSH (POMC, P01189), β-MSH (POMC, P01189) > ACTH (POMC, P01189), α-MSH (POMC, P01189)

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]NDP-MSH Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 9.7 pKd 16
pKd 9.7 (Kd 2x10-10 M) [16]
γ-MSH {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Hs Full agonist 8.5 pKd 23
pKd 8.5 [23]
AP1189 Small molecule or natural product Hs Biased agonist 6.4 pKd 2
pKd 6.4 (Kd 3.6x10-7 M) [2]
afamelanotide Peptide Approved drug Click here for species-specific activity table Hs Full agonist 8.9 pKi 1
pKi 8.9 [1]
MT-II Peptide Click here for species-specific activity table Hs Full agonist 8.3 pKi 1
pKi 8.3 [1]
α-MSH {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.0 – 8.4 pKi 1,23
pKi 8.0 – 8.4 [1,23]
setmelanotide Peptide Approved drug Click here for species-specific activity table Hs Agonist 8.0 pKi 17
pKi 8.0 (Ki 1x10-8 M) [17]
bremelanotide Peptide Approved drug Click here for species-specific activity table Hs Agonist 7.3 pKi 6
pKi 7.3 (Ki 5.3x10-8 M) [6]
Description: Inhibition of 125I-NDP-αMSH binding to membranes from BHK570 cells stably expressing human MC3 receptor.
ACTH {Sp: Human} Peptide Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 7.1 pKi 26
pKi 7.1 (Ki 8.69x10-8 M) [26]
[D-Trp8]γ-MSH Peptide Hs Full agonist 8.2 pIC50 10
pIC50 8.2 (IC50 6.31x10-9 M) [10]
Agonist Comments
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 Value Parameter Reference
HS024 Peptide Click here for species-specific activity table Hs Antagonist 8.3 pKd 14
pKd 8.3 [14]
HS014 Peptide Click here for species-specific activity table Hs Antagonist 7.3 pKd 27
pKd 7.3 [27]
SHU9119 Peptide Rn Antagonist 9.1 pKi 1
pKi 9.1 (Ki 8.79x10-10 M) [1]
SHU9119 Peptide Click here for species-specific activity table Hs Antagonist 8.9 – 9.1 pKi 13,19,27
pKi 8.9 – 9.1 [13,19,27]
PG-901 Peptide Click here for species-specific activity table Hs Antagonist 9.7 pIC50 12
pIC50 9.7 [12]
agouti-related protein {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Inverse agonist 7.7 pIC50 25
pIC50 7.7 [25]
agouti {Sp: Mouse} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Mm Inverse agonist 6.7 pIC50 15
pIC50 6.7 [15]
PG-106 Peptide Hs Antagonist 6.7 pIC50 11
pIC50 6.7 (IC50 2.1x10-7 M) [11]
[125I]SHU9119 Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - - 22
[22]
View species-specific antagonist tables
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  9
Secondary Transduction Mechanisms Click here for help
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:  20,29
Tissue Distribution Click here for help
Stomach, duodenum and pancreas.
Species:  Human
Technique:  PCR and Southern Blotting.
References:  9
Heart.
Species:  Human
Technique:  PCR and hybridisation.
References:  5
Placenta.
Species:  Human
Technique:  Northern blotting.
References:  9
Brain: Cortex, thalamus, hippocampus, hypothalamus.
Species:  Mouse
Technique:  in situ hybridisation.
References:  9
Brain.
Species:  Rat
Technique:  Northern blotting.
References:  9
Brain: Mainly found in the hypothalamus, but small amounts found in other brain regions.
Species:  Rat
Technique:  Northern Blotting and in situ hybridisation.
References:  24
Expression Datasets Click here for help

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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 Click here for help
Measurement of cAMP levels in cells transfected with the MC3 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Increase in cAMP.
References:  30
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:  20
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:  9
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:  7
Physiological Functions Click here for help
Naturesis.
Species:  Mouse
Tissue:  In vivo.
References:  21
Energy homeostasis.
Species:  Mouse
Tissue:  In vivo
References:  3-4
Physiological Consequences of Altering Gene Expression Click here for help
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:  4
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:  3
Phenotypes, Alleles and Disease Models Click here for help 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 Click here for help
Disease:  Obesity due to MC3R deficiency
OMIM: 602025
Orphanet: ORPHA217031
Comments: 

References

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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 Pharmacol, 378: 249-258. [PMID:10493100]

2. Boman A, Jonassen TEN, Lundstedt T. (2007) Phenyl pyrrole aminoguanidine derivatives. Patent number: WO2007141343A1. Assignee: Action Pharma A/S. Priority date: 09/06/2006. Publication date: 13/12/2007.

3. 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. Endocrinology, 141 (9): 3518-21. [PMID:10965927]

4. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L et al.. (2000) Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet, 26 (1): 97-102. [PMID:10973258]

5. Chhajlani V. (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int, 38 (1): 73-80. [PMID:8932521]

6. Conde-Frieboes K, Thøgersen H, Lau JF, Sensfuss U, Hansen TK, Christensen L, Spetzler J, Olsen HB, Nilsson C, Raun K et al.. (2012) Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues. J Med Chem, 55 (5): 1969-77. [PMID:22335602]

7. Daniels D, Suzuki A, Shapiro E, Luo L, Yee DK, Fluharty SJ. (2005) Rattus norvegicus melanocortin 3 receptor: a corrected sequence. Peptides, 26 (10): 1835-41. [PMID:15985309]

8. 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 ( Pt 2): 367-73. [PMID:8172596]

9. 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 (11): 8246-50. [PMID:8463333]

10. Grieco P, Balse PM, Weinberg D, MacNeil T, Hruby VJ. (2000) D-Amino acid scan of gamma-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity. J Med Chem, 43 (26): 4998-5002. [PMID:11150170]

11. 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. Peptides, 28 (6): 1191-6. [PMID:17482720]

12. 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 (24): 5287-94. [PMID:12431055]

13. Hruby VJ, Lu D, Sharma SD, Castrucci AL, Kesterson RA, al-Obeidi FA, Hadley ME, Cone RD. (1995) Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem, 38 (18): 3454-61. [PMID:7658432]

14. 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. Endocrinology, 139 (12): 5006-14. [PMID:9832440]

15. Kiefer LL, Veal JM, Mountjoy KG, Wilkison WO. (1998) Melanocortin receptor binding determinants in the agouti protein. Biochemistry, 37 (4): 991-7. [PMID:9454589]

16. 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 Pharmacol, 512 (2-3): 85-95. [PMID:15840392]

17. Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, Culler MD, Yang H, Dixit VD, Butler AA. (2009) Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides, 30 (10): 1892-900. [PMID:19646498]

18. Liang J, Li L, Jin X, Xu B, Pi L, Liu S, Zhu W, Zhang C, Luan B, Gong L et al.. (2018) Pharmacological effect of human melanocortin-2 receptor accessory protein 2 variants on hypothalamic melanocortin receptors. Endocrine, 61 (1): 94-104. [PMID:29704154]

19. MacNeil DJ, Howard AD, Guan X, Fong TM, Nargund RP, Bednarek MA, Goulet MT, Weinberg DH, Strack AM, Marsh DJ et al.. (2002) The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. Eur J Pharmacol, 440 (2-3): 141-57. [PMID:12007532]

20. Mountjoy KG, Kong PL, Taylor JA, Willard DH, Wilkison WO. (2001) Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells. Physiol Genomics, 5 (1): 11-9. [PMID:11161002]

21. 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 (8): 1251-8. [PMID:12697744]

22. Nickolls SA, Cismowski MI, Wang X, Wolff M, Conlon PJ, Maki RA. (2003) Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity. J Pharmacol Exp Ther, 304 (3): 1217-27. [PMID:12604699]

23. 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 (24): 16853-60. [PMID:10358030]

24. Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RD. (1993) Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci USA, 90 (19): 8856-60. [PMID:8415620]

25. Rosenfeld RD, Zeni L, Welcher AA, Narhi LO, Hale C, Marasco J, Delaney J, Gleason T, Philo JS, Katta V et al.. (1998) Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein. Biochemistry, 37 (46): 16041-52. [PMID:9819197]

26. Schioth HB, Muceniece R, Wikberg JE, Chhajlani V. (1995) Characterisation of melanocortin receptor subtypes by radioligand binding analysis. Eur J Pharmacol, 288 (3): 311-317. [PMID:7774675]

27. Schiöth 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. Neuropeptides, 33 (3): 191-6. [PMID:10657491]

28. Schiöth 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 (3): 381-4. [PMID:8957262]

29. 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. Neuropeptides, 37 (4): 201-10. [PMID:12906838]

30. Yang YK, Dickinson C, Lai YM, Li JY, Gantz I. (2001) Functional properties of an agouti signaling protein variant and characteristics of its cognate radioligand. Am J Physiol Regul Integr Comp Physiol, 281 (6): R1877-86. [PMID:11705773]

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