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MC5 receptor

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Target not currently curated in GtoImmuPdb

Target id: 286

Nomenclature: MC5 receptor

Family: Melanocortin receptors

Contents:

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 7 325 18p11.21 MC5R melanocortin 5 receptor 5
Mouse 7 325 18 41.46 cM Mc5r melanocortin 5 receptor 7,15
Rat 7 325 18q12.1 Mc5r melanocortin 5 receptor 9
Previous and Unofficial Names Click here for help
MC5R | melanocortin receptor 5
Database Links Click here for help
Specialist databases
GPCRdb mc5r_human (Hs), mc5r_mouse (Mm), mc5r_rat (Rn)
Other databases
Alphafold P33032 (Hs), P41149 (Mm), P35345 (Rn)
ChEMBL Target CHEMBL4608 (Hs), CHEMBL4489 (Mm), CHEMBL2701 (Rn)
Ensembl Gene ENSG00000176136 (Hs), ENSMUSG00000007480 (Mm), ENSRNOG00000016685 (Rn)
Entrez Gene 4161 (Hs), 17203 (Mm), 25726 (Rn)
Human Protein Atlas ENSG00000176136 (Hs)
KEGG Gene hsa:4161 (Hs), mmu:17203 (Mm), rno:25726 (Rn)
OMIM 600042 (Hs)
Pharos P33032 (Hs)
RefSeq Nucleotide NM_005913 (Hs), NM_013596 (Mm), NM_013182 (Rn)
RefSeq Protein NP_005904 (Hs), NP_038624 (Mm), NP_037314 (Rn)
UniProtKB P33032 (Hs), P41149 (Mm), P35345 (Rn)
Wikipedia MC5R (Hs)
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: α-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)
α-MSH (POMC, P01189) > β-MSH (POMC, P01189) > ACTH (POMC, P01189) > γ-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
SHU9119 Peptide Click here for species-specific activity table Hs Partial agonist 9.0 pKd 20
⤷ pKd 9.0 [20]
[125I]NDP-MSH Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 8.6 pKd 13
⤷ pKd 8.6 (Kd 2.8x10-9 M) [13]
α-MSH {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 6.9 pKd 16
⤷ pKd 6.9 [16]
bremelanotide Peptide Approved drug Click here for species-specific activity table Hs Agonist 7.8 pKi 6
⤷ pKi 7.8 (Ki 1.7x10-8 M) [6]
Description: Inhibition of 125I-NDP-αMSH binding to membranes from BHK570 cells stably expressing human MC5 receptor.
setmelanotide Peptide Approved drug Click here for species-specific activity table Hs Agonist 6.4 pKi 14
⤷ pKi 6.4 (Ki 4.3x10-7 M) [14]
ACTH {Sp: Human} Peptide Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist <5.0 pKi 19
⤷ pKi <5.0 (Ki >1x10-5 M) [19]
PG-901 Peptide Click here for species-specific activity table Hs Full agonist 10.5 pIC50 8
⤷ pIC50 10.5 [8]
MT-II Peptide Click here for species-specific activity table Hs Full agonist 9.0 pIC50 16
⤷ pIC50 9.0 [16]
afamelanotide Peptide Approved drug Click here for species-specific activity table Hs Full agonist 9.0 pIC50 16
⤷ pIC50 9.0 [16]
Agonist Comments
α-MSH, NDP-MSH, MT-II and ACTH (1-24) are > 10-fold more potent at the rhesus MC5 than human MC5 [10].
Antagonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
HS024 Peptide Click here for species-specific activity table Hs Antagonist 8.5 pKd 11
⤷ pKd 8.5 [11]
agouti {Sp: Mouse} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Mm Inverse agonist 4.9 pKd 12
⤷ pKd 4.9 [12]
Ac-c[Cys-Glu-His-D-Phe-Arg-Trp-D-Cys]-Pro-Pro-Lys-Asp-NH2 Peptide Hs Antagonist 8.0 pIC50 1
⤷ pIC50 8.0 [1]
agouti-related protein {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Inverse agonist 6.5 pIC50 23
⤷ pIC50 6.5 [23]
View species-specific antagonist tables
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  15
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
G protein (identity unknown) Other - See Comments
Comments:  Melanocortin activation of the MC5 mobilizes intracellular calcium via an incompletely understood pathway(s).
References:  17
Tissue Distribution Click here for help
Adrenal gland, fat cells, kidney, leukocytes, lung, lymph node, mammary gland, ovary, pituitary, testis and uterus.
Species:  Human
Technique:  PCR and hybridisation.
References:  4
Adipose tissue.
Species:  Mouse
Technique:  RT-PCR and Northern Blotting.
References:  2
Harderian, preputial and lacrimal glands.
Species:  Mouse
Technique:  Radioligand binding.
References:  3
Exocrine glands: Extraorbital lacrimal, Harderian, preputial, and prostate glands.
Pancreas, adrenal glands, esophagus and thymus.
Species:  Rat
Technique:  RNase protection assay.
References:  21
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 Ca2+ in a HEK 293 cell line transfected with the MC5 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Mobilization of [Ca2+]i.
References:  17
Measurement of cAMP in cell lines transfected with the MC5 receptor.
Species:  Human
Tissue:  HEK 293 and COS cells.
Response measured:  Intracellular cAMP accumulation.
References:  15
Measurment of cAMP levels in cells transfected with the MC5 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Increase in cAMP.
References:  22
Measurment of cAMP levels and leptin expression in 3T3-L1 adipocyte cells expressing both MC2 and MC5 receptors.
Species:  Human
Tissue:  3T3-L1 cell line.
Response measured:  Increase in cAMP production and decrease in leptin expression.
References:  18
Measurement of cAMP accumulation in CHO cells stably transfected with the rat MC5 receptor.
Species:  Rat
Tissue:  CHO cells.
Response measured:  Increase in cAMP accumulation.
References:  9
Physiological Functions Click here for help
Sebum production.
Species:  Mouse
Tissue:  Hair follicle-associated sebaceous glands.
References:  3
Physiological Consequences of Altering Gene Expression Click here for help
Mice with targeted deletion of the MC5 receptor have a defect in water and thermoregulation secondary to their decreased production of sebaceous lipids.
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
Mc5rtm1Cone Mc5rtm1Cone/Mc5rtm1Cone
involves: 129S4/SvJaeSor * 129S6/SvEvTac		 MGI:99420  MP:0001777 abnormal body temperature regulation PMID: 9413988 
Mc5rtm1Cone Mc5rtm1Cone/Mc5rtm1Cone
involves: 129S4/SvJaeSor * 129S6/SvEvTac		 MGI:99420  MP:0000367 abnormal coat/ hair morphology PMID: 9413988 
Mc5rtm1Cone Mc5rtm1Cone/Mc5rtm1Cone
involves: 129S4/SvJaeSor * 129S6/SvEvTac		 MGI:99420  MP:0003859 abnormal Harderian gland physiology PMID: 9413988 
Mc5rtm1Cone Mc5rtm1Cone/Mc5rtm1Cone
B6.129S4-Mc5r		 MGI:99420  MP:0003859 abnormal Harderian gland physiology PMID: 9413988 
Mc5rtm1Cone Mc5rtm1Cone/Mc5rtm1Cone
involves: 129S4/SvJaeSor * 129S6/SvEvTac		 MGI:99420  MP:0001348 abnormal lacrimal gland physiology PMID: 9413988 
Mc5rtm1Cone Mc5rtm1Cone/Mc5rtm1Cone
involves: 129S4/SvJaeSor * 129S6/SvEvTac		 MGI:99420  MP:0002992 abnormal sebaceous lipid secretion PMID: 9413988 
Mc5rtm1Cone Mc5rtm1Cone/Mc5rtm1Cone
B6.129S4-Mc5r		 MGI:99420  MP:0003862 decreased aggression towards males PMID: 14733892 

References

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1. Balse-Srinivasan P, Grieco P, Cai M, Trivedi D, Hruby VJ. (2003) Structure-activity relationships of novel cyclic alpha-MSH/beta-MSH hybrid analogues that lead to potent and selective ligands for the human MC3R and human MC5R. J Med Chem, 46 (17): 3728-33. [PMID:12904077]

2. Boston BA, Cone RD. (1996) Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3-L1 cell line. Endocrinology, 137 (5): 2043-50. [PMID:8612546]

3. Chen W, Kelly MA, Opitz-Araya X, Thomas RE, Low MJ, Cone RD. (1997) Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell, 91 (6): 789-98. [PMID:9413988]

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

5. Chhajlani V, Muceniece R, Wikberg JE. (1993) Molecular cloning of a novel human melanocortin receptor. Biochem Biophys Res Commun, 195 (2): 866-73. [PMID:8396929]

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. Gantz I, Shimoto Y, Konda Y, Miwa H, Dickinson CJ, Yamada T. (1994) Molecular cloning, expression, and characterization of a fifth melanocortin receptor. Biochem Biophys Res Commun, 200 (3): 1214-20. [PMID:8185570]

8. 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]

9. Griffon N, Mignon V, Facchinetti P, Diaz J, Schwartz JC, Sokoloff P. (1994) Molecular cloning and characterization of the rat fifth melanocortin receptor. Biochem Biophys Res Commun, 200 (2): 1007-14. [PMID:8179577]

10. Huang RR, Singh G, Van der Ploeg LH, Fong TM. (2000) Species-dependent pharmacological properties of the melanocortin-5 receptor. J Recept Signal Transduct Res, 20 (1): 47-59. [PMID:10711496]

11. 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]

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

13. 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]

14. 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]

15. Labbe O, Desarnaud F, Eggerickx D, Vassart G, Parmentier M. (1994) Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. Biochemistry, 33: 4543-4549. [PMID:8161509]

16. 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]

17. 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]

18. Norman D, Isidori AM, Frajese V, Caprio M, Chew SL, Grossman AB, Clark AJ, Michael Besser G, Fabbri A. (2003) ACTH and alpha-MSH inhibit leptin expression and secretion in 3T3-L1 adipocytes: model for a central-peripheral melanocortin-leptin pathway. Mol Cell Endocrinol, 200 (1-2): 99-109. [PMID:12644303]

19. 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]

20. 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]

21. van der Kraan M, Adan RA, Entwistle ML, Gispen WH, Burbach JP, Tatro JB. (1998) Expression of melanocortin-5 receptor in secretory epithelia supports a functional role in exocrine and endocrine glands. Endocrinology, 139 (5): 2348-55. [PMID:9564844]

22. 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]

23. Yang YK, Thompson DA, Dickinson CJ, Wilken J, Barsh GS, Kent SB, Gantz I. (1999) Characterization of Agouti-related protein binding to melanocortin receptors. Mol Endocrinol, 13 (1): 148-55. [PMID:9892020]

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