Biology:ACTH receptor

Short description: Mammalian protein found in Homo sapiens

Generic protein structure example

The adrenocorticotropic hormone receptor or ACTH receptor also known as the melanocortin receptor 2 or MC₂ receptor is a type of melanocortin receptor (type 2) which is specific for ACTH. A G protein–coupled receptor located on the external cell plasma membrane, it is coupled to G_αs and upregulates levels of cAMP by activating adenylyl cyclase. The ACTH receptor plays a role in immune function and glucose metabolism.

Structure

ACTH receptors are the shortest of the melanocortin receptor family and are the smallest known G-coupled receptors. Both human and bovine ACTH receptors are synthesized as 297 residue long proteins with 81% sequence homology. There are currently no available protein X-ray crystallography structures for the ACTH receptor available in the Protein Data Bank; while the ACTH receptor and the β₂ adrenergic receptor are relatively distantly-related with a sequence identity of approximately 26%, MC2R investigators such as David Fridmanis have assumed that the folded surfaces of both receptors that are responsible for binding G_αs should be very similar and use conserved motifs.

The full length sequence of MC2R includes seven hydrophobic domains that are predicted as transmembrane segments. In the third intracellular loop of the receptor a protein kinase A and protein kinase c phosphorylation motifs have been detected. ACTH receptors also require the binding of melanocortin-2 receptor accessory protein-1 (MRAP1) without which ACTH receptors cannot bind ACTH. Without MRAP, the receptor is degraded in the endoplasmic reticulum, but with MRAP, the receptor is glycosylated and expressed on the cell plasma membrane.

Ligands

MCR's have both endogenous agonists and antagonists.

Agonists

α-MSH and ACTH are both peptides derived from processed POMC, and both activate the other MCR's, but ACTH is the only agonist ligand for MC2R (ACTH receptor). This suggests that there is more protein-related specificity for binding MC2R.

Antagonists

Agouti-related protein and Agouti-signaling protein are antagonist peptides to MC2R.

Tissue and subcellular localization

ACTH receptor is primarily found in the zona fasciculata of the human adrenal cortex. Binding of the receptor by ACTH stimulates the production of glucocorticoids (GCs)—by contrast, aldosterone production from the zona glomerulosa is stimulated primarily by angiotensin II. ACTH receptors are also expressed in the skin, and in both white and brown adipocytes, and is expressed in greater concentrations when adipose cells differentiate.

It is well known that levels of corticosterone (CORT, cortisol in humans) secretion demonstrate a circadian rhythm, highly regulated by effects of the suprachiasmatic nucleus, with higher levels in the early evening and lower levels in the morning. ACTH levels, ACTH receptor expression, and MRAP1 expression also demonstrate circadian rhythm, with ACTH secretion and MRAP expression highest in the evening, suggesting that MRAP expression is responsible for CORT secretory regulation. However, with exposure to constant light, the rhythmic expression of the ACTH receptor and MRAP genes reversed, suggesting ACTH-independent signalling pathways for MRAP and ACTH receptor transcription and expression.

Clinical significance

The ACTH receptor plays a role in glucose metabolism when expressed in white adipose cells. When bound to ACTH, a short-term insulin-resistance occurs, and it stimulates lipolysis via hormone sensitive lipase. Demonstrated in mice, ACTH promotes lipolysis in response to increased energy demand, notably in times of stress. Lipolytic activity due to melanocortin receptors has been demonstrated in several types of test animals: rats and hamsters primarily respond to ACTH, rabbits respond to alpha and beta MSH's (therefore not using the ACTH receptor), and guinea pigs responding to both ACTH and other MSH's. In humans, ACTH has little lipolytic effect on adipose tissue.

ACTH receptor activation also influences immune function. Melanocortins, including ACTH, have anti-inflammatory effects which can be exerted via GC-dependent and -independent pathways. The GC-dependent pathway activates ACTH receptors to increase levels of cortisol which bind GC receptors. Via genomic and faster non-genomic pathways, this causes, among other immune responses, a reduction in leukocyte and neutrophil infiltration, cytokine production, especially of cytokine CXCL-1, and increased phagocytosis of apoptotic neutrophils. These profound anti-inflammatory effects and the ability to increase GC's are why ACTH therapy is still used today. It is often used as treatment for infantile spasms, multiple sclerosis, nephrotic syndrome, gout, ulcerative colitis, Crohn's disease, rheumatoid arthritis, and systemic lupus erythematosus. This is problematic long-term and can lead to ACTH-receptor pathway-related side effects including: Cushing's syndrome, fluid retention, glaucoma, and cardiovascular disorders.

Mutations in this receptor cause familial glucocorticoid deficiency (FGD) type 1, in which patients have high levels of serum ACTH and low levels of cortisol. Mutation of the receptor gene causes 25% of FGD, and mutation on the MRAP gene causes 20% of FGD. Mutations of ACTH can also contribute to this pathology: mutation of the "message sequence" inhibits cAMP production when bound to the ACTH receptor, and mutation of the "address sequence" inhibits binding to the receptor altogether.

Evolution

Paralogue

Source:

• MC4R
• MC3R
• MC5R
• MC1R
• GPR12
• S1PR1
• S1PR2
• LPAR1
• CNR1
• S1PR3
• GPR6
• GPR3
• S1PR5
• LPAR3
• S1PR4
• CNR2
• GPR119
• LPAR2

See also

• melanocortin

Further reading

• "Cloning and functional characterization of a family of receptors for the melanotropic peptides". Annals of the New York Academy of Sciences 680 (1): 342–63. May 1993. doi:10.1111/j.1749-6632.1993.tb19694.x. PMID 8390157. Bibcode: 1993NYASA.680..342C. 
• "Adrenocorticotropin receptor and adrenal disorders". Hormone Research 47 (4–6): 273–8. 1997. doi:10.1159/000185476. PMID 9167964. 
• "Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides". Neuroimmunomodulation 3 (5): 259–84. 1997. doi:10.1159/000097281. PMID 9218248. 
• "The cloning of a family of genes that encode the melanocortin receptors". Science 257 (5074): 1248–51. August 1992. doi:10.1126/science.1325670. PMID 1325670. Bibcode: 1992Sci...257.1248M. 
• "Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor". Lancet 341 (8843): 461–2. February 1993. doi:10.1016/0140-6736(93)90208-X. PMID 8094489. 
• "Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene". The Journal of Clinical Investigation 92 (5): 2458–61. November 1993. doi:10.1172/JCI116853. PMID 8227361. 
• "Localization of the genes encoding the melanocortin-2 (adrenocorticotropic hormone) and melanocortin-3 receptors to chromosomes 18p11.2 and 20q13.2-q13.3 by fluorescence in situ hybridization". Genomics 18 (1): 166–7. October 1993. doi:10.1006/geno.1993.1448. PMID 8276410. https://deepblue.lib.umich.edu/bitstream/2027.42/30538/1/0000171.pdf. 
• "Molecular cloning of a novel melanocortin receptor". The Journal of Biological Chemistry 268 (11): 8246–50. April 1993. doi:10.1016/S0021-9258(18)53088-X. PMID 8463333. 
• "Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency". The Journal of Clinical Endocrinology and Metabolism 81 (4): 1442–8. April 1996. doi:10.1210/jcem.81.4.8636348. PMID 8636348. 
• "Genomic structure and promoter characterization of the human ACTH receptor gene". Biochemical and Biophysical Research Communications 230 (1): 7–12. January 1997. doi:10.1006/bbrc.1996.5911. PMID 9020063. 
• "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology 11 (3): 274–80. March 1997. doi:10.1210/mend.11.3.9898. PMID 9058374. 
• "Stable expression of normal and mutant human ACTH receptor: study of ACTH binding and coupling to adenylate cyclase". Molecular and Cellular Endocrinology 129 (1): 83–90. April 1997. doi:10.1016/S0303-7207(97)04043-4. PMID 9175632. 
• "Presence of multiple functional polyadenylation signals in the 3′-untranslated region of human corticotropin receptor cDNA". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1356 (3): 249–52. May 1997. doi:10.1016/S0167-4889(97)00031-1. PMID 9194567. 
• "Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH". Clinical Endocrinology 53 (3): 389–92. September 2000. doi:10.1046/j.1365-2265.2000.01040.x. PMID 10971458. 
• "Clinical, genetic, and functional characterization of adrenocorticotropin receptor mutations using a novel receptor assay". The Journal of Clinical Endocrinology and Metabolism 87 (9): 4318–23. September 2002. doi:10.1210/jc.2002-020501. PMID 12213892. 
• "Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity". Molecular Endocrinology 16 (12): 2746–53. December 2002. doi:10.1210/me.2002-0099. PMID 12456795. 
• "Differential regulation of the human adrenocorticotropin receptor [melanocortin-2 receptor (MC2R)] by human MC2R accessory protein isoforms alpha and beta in isogenic human embryonic kidney 293 cells". Molecular Endocrinology 21 (7): 1656–69. July 2007. doi:10.1210/me.2007-0041. PMID 17456795. 

External links

• "Melanocortin Receptors: MC₂". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2350. 
• MC2+Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human MC2R genome location and MC2R gene details page in the UCSC Genome Browser.