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

MC2 receptor

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

   GtoImmuPdb view: OFF :     Currently no data for MC2 receptor in GtoImmuPdb

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 ligands (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 Affinity Units 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 Affinity Units 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: 2043-2050. [PMID:8612546]

2. Chhajlani V. (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int., 38: 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: 461-462. [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: 3291-3294. [PMID:8754753]

5. Kojima I, Kojima K, Rasmussen H. (1985) Characteristics of angiotensin II-, K+- and ACTH-induced calcium influx in adrenal glomerulosa cells. Evidence that angiotensin II, K+, and ACTH may open a common calcium channel. J. Biol. Chem., 260: 9171-9176. [PMID:2579947]

6. Kubo M, Ishizuka T, Kijima H, Kakinuma M, Koike T. (1995) Cloning of a mouse adrenocorticotropin receptor-encoding gene. Gene, 153: 279-280. [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: 1248-1251. [PMID:1325670]

8. Naville D, Barjhoux L, Jaillard C, Saez JM, Durand P, Begeot M. (1997) Stable expression of normal and mutant human ACTH receptor: study of ACTH binding and coupling to adenylate cyclase. Mol. Cell Endocrinol., 129: 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: 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: 1842-1847. [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: 164-171. [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: 2746-2746. [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: 2746-2753. [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: 63-68. [PMID:8781213]

15. 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]

Contributors

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How to cite this page

Tung M. 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: MC2 receptor. Last modified on 20/02/2018. Accessed on 17/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=283.