MC<sub>2</sub> receptor | Melanocortin receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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MC2 receptor

Target not currently curated in GtoImmuPdb

Target id: 283

Nomenclature: MC2 receptor

Family: Melanocortin receptors

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

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 297 18p11.21 MC2R melanocortin 2 receptor 7
Mouse 7 296 18 E2 Mc2r melanocortin 2 receptor 6
Rat 7 296 18p12.1 Mc2r melanocortin 2 receptor
Previous and Unofficial Names
ACTHR | melanocortin 2 receptor | adrenocorticotropic hormone receptor | melanocortin 2 receptor (adrenocorticotropic hormone)
Database Links
Specialist databases
GPCRDB acthr_human (Hs), acthr_mouse (Mm)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
ACTH {Sp: Human} , ACTH {Sp: Mouse, Rat}
Comments: 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)
ACTH (POMC, P01189)

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ACTH {Sp: Mouse, Rat} Mm Full agonist 9.8 pKd 4
pKd 9.8 [4]
ACTH-(1-24) Mm Full agonist 9.1 pKd 4
pKd 9.1 [4]
corticotrophin-releasing hormone {Sp: Human, Mouse, Rat} Hs Agonist - -
[125I]ACTH-(1-24) Hs Full agonist - -
cosyntropin Hs Agonist - -
corticotropin zinc hydroxide Hs Agonist - -
View species-specific agonist tables
Agonist Comments
The MC2 receptor is the primary target for the approved drugs ACTH, cosyntropin, seractide acetate and corticotrophin zinc hydroxide.

Radioligands include [125I]ACTH, [125I-Tyr23]ACTH, and [125I](Phe2,Nle4)ACTH(1-24).

The MC2 receptor only binds ACTH and does not bind the other melanocortin peptides α-, β-, and γ-MSH.
Antagonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ACTH-(11-24) Hs Antagonist 9.0 pKd 4
pKd 9.0 [4]
ASIP [90-132 (L89Y)] Hs Inverse agonist 7.3 pIC50 15
pIC50 7.3 [15]
Antagonist Comments
Human agouti is an selective, endogenous, inverse agonist whose affinity has not yet been established. It is referred to in the literature as agouti-signaling protein (ASP or ASIP).

[125I]ASIP [90-132 (L89Y)] has been used as a radioligand [15].
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  8
Secondary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown) Calcium channel
References:  5
Tissue Distribution
Adrenal gland.
Species:  Human
Technique:  PCR and hybridisation.
References:  2
Skin tissue.
Species:  Human
Technique:  RT-PCR and Southern Hybridisation.
References:  12
White adipose tissue.
Species:  Mouse
Technique:  RT-PCR and Northern Blotting.
References:  1
Adrenal cortex: Strong labelling in the zona glomerulosa and zona fasciculata. Less labelling in the zona reticularis.
Adrenal medulla: Labelling of a few scattered cells.
Species:  Mouse
Technique:  in situ hybridisation.
References:  14
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 the level of circulating glucocorticoids and steroidogenic enzymes in the adrenal cortex.
Species:  Human
Tissue:  Adrenal cortex
Response measured:  Elevation of circulating glucocorticoids and of steroidogenic enzymes.
References: 
Measurement of intracellular cAMP levels in OS3 cells transfected with the MC2 receptor.
Species:  Human
Tissue:  OS3 cells.
Response measured:  Increased cAMP levels.
References:  15
Measurement of cAMP levels in mouse cloudman S91 melanoma cells (M3 cells) stably transfected with the MC2 receptor.
Species:  Human
Tissue:  M3 cells.
Response measured:  Increased cAMP levels.
References:  8
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:  9
Functional Assay Comments
For unknown reasons, it has been difficult to express the human MC2 in non-adrenal cell lines [11]. Reference [10] describes the transfection of the human MC2 receptor into murine M3 melanoma cells and HEK293 cells. In the M3 cells, the receptor was expressed in the membrane to form a functional receptor, whereas in HEK293 cells it remained intracellular.
Physiological Functions
"Classical ACTH" receptor that is involved in adrenal cortical steroidogenesis.
Species:  Human
Tissue:  Adrenal cortex
References:  7
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0000639 abnormal adrenal gland morphology PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0003383 abnormal gluconeogenesis PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0002078 abnormal glucose homeostasis PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0000640 adrenal gland hypoplasia PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0005661 decreased circulating adrenaline level PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0002667 decreased circulating aldosterone level PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0002665 decreased circulating corticosterone level PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0005333 decreased heart rate PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0010025 decreased total body fat amount PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0000189 hypoglycemia PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0001748 increased circulating adrenocorticotropin level PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0003019 increased circulating chloride level PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0005627 increased circulating potassium level PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0004952 increased spleen weight PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0004955 increased thymus weight PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0005202 lethargy PMID: 17989225 
Mc2rtm1Dchi Mc2rtm1Dchi/Mc2rtm1Dchi
B6.129P2-Mc2r
MGI:96928  MP:0002082 postnatal lethality PMID: 17989225 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Glucocorticoid deficiency 1; GCCD1
Synonyms: Familial glucocorticoid deficiency [Orphanet: ORPHA361]
OMIM: 202200
Orphanet: ORPHA361
Comments: 
References:  3
Biologically Significant Variants
Type:  Naturally occurring mutation
Species:  Human
Description:  Constitutively active human MC2 receptor found in an individual with ACTH-independent Cushing's syndrome. Variant MC2 receptor is associated with elevated basal cAMP accumulation and failure to desensitize.
References:  13

References

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1. 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]

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

3. Clark AJ, McLoughlin L, Grossman A. (1993) Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet, 341 (8843): 461-2. [PMID:8094489]

4. Kapas S, Cammas FM, Hinson JP, Clark AJ. (1996) Agonist and receptor binding properties of adrenocorticotropin peptides using the cloned mouse adrenocorticotropin receptor expressed in a stably transfected HeLa cell line. Endocrinology, 137 (8): 3291-4. [PMID:8754753]

5. Kojima I, Kojima K, Rasmussen H. (1985) Role of calcium and cAMP in the action of adrenocorticotropin on aldosterone secretion. J. Biol. Chem., 260 (7): 4248-56. [PMID:2579947]

6. Kubo M, Ishizuka T, Kijima H, Kakinuma M, Koike T. (1995) Cloning of a mouse adrenocorticotropin receptor-encoding gene. Gene, 153 (2): 279-80. [PMID:7875603]

7. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. (1992) The cloning of a family of genes that encode the melanocortin receptors. Science, 257 (5074): 1248-51. [PMID:1325670]

8. Naville D, Barjhoux L, Jaillard C, Saez JM, Durand P, Bégeot M. (1997) Stable expression of normal and mutant human ACTH receptor: study of ACTH binding and coupling to adenylate cyclase. Mol. Cell. Endocrinol., 129 (1): 83-90. [PMID:9175632]

9. 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]

10. Rached M, El Mourabit H, Buronfosse A, Blondet A, Naville D, Begeot M, Penhoat A. (2005) Expression of the human melanocortin-2 receptor in different eukaryotic cells. Peptides, 26 (10): 1842-7. [PMID:15982783]

11. Schimmer BP, Kwan WK, Tsao J, Qiu R. (1995) Adrenocorticotropin-resistant mutants of the Y1 adrenal cell line fail to express the adrenocorticotropin receptor. J. Cell. Physiol., 163 (1): 164-71. [PMID:7896893]

12. Slominski A, Ermak G, Mihm M. (1996) ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin. J. Clin. Endocrinol. Metab., 81 (7): 2746-9. [PMID:8675607]

13. Swords FM, Baig A, Malchoff DM, Malchoff CD, Thorner MO, King PJ, Hunyady L, Clark AJ. (2002) Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity. Mol. Endocrinol., 16 (12): 2746-53. [PMID:12456795]

14. Xia Y, Wikberg JE. (1996) Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal gland. Cell Tissue Res., 286 (1): 63-8. [PMID:8781213]

15. 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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