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.[5] A G protein–coupled receptor located on the external cell plasma membrane, it is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase.[6][7][8] The ACTH receptor plays a role in immune function and glucose metabolism.[9]
Structure
ACTH receptors are the shortest of the melanocortin receptor family and are the smallest known G-coupled receptors.[10] Both human and bovine ACTH receptors are synthesized as 297 residue long proteins with 81% sequence homology.[11] There are currently no available proteinX-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 Gαs should be very similar and use conserved motifs.[6]
The full length sequence of MC2R includes seven hydrophobic domains that are predicted as transmembrane segments.[11] In the third intracellular loop of the receptor a protein kinase A and protein kinase c phosphorylation motifs have been detected.[11] ACTH receptors also require the binding of melanocortin-2 receptor accessory protein-1 (MRAP1) without which ACTH receptors cannot bind ACTH.[10] Without MRAP, the receptor is degraded in the endoplasmic reticulum, but with MRAP, the receptor is glycosylated and expressed on the cell plasma membrane.[12]
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.[13][10]
Antagonists
Agouti-related protein and Agouti-signaling protein are antagonist peptides to MC2R.[10]
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.[15] 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.[15]
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.[16] 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.[17]
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.[19][20] 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.[10]
^Iwen KA, Senyaman O, Schwartz A, Drenckhan M, Meier B, Hadaschik D, Klein J (March 2008). "Melanocortin crosstalk with adipose functions: ACTH directly induces insulin resistance, promotes a pro-inflammatory adipokine profile and stimulates UCP-1 in adipocytes". The Journal of Endocrinology. 196 (3): 465–72. doi:10.1677/JOE-07-0299. PMID18310442. S2CID207255622.
^ abPark SY, Walker JJ, Johnson NW, Zhao Z, Lightman SL, Spiga F (May 2013). "Constant light disrupts the circadian rhythm of steroidogenic proteins in the rat adrenal gland". Molecular and Cellular Endocrinology. Fifteenth Conference on the Adrenal Cortex (Adrenal 2012) League City, Texas June 19 – 22, 2012. 371 (1–2): 114–23. doi:10.1016/j.mce.2012.11.010. PMID23178164. S2CID32479803.
^ abMontero-Melendez T (May 2015). "ACTH: The forgotten therapy". Seminars in Immunology. Resolution of inflammation. 27 (3): 216–26. doi:10.1016/j.smim.2015.02.003. PMID25726511.
^Clark AJ, McLoughlin L, Grossman A (February 1993). "Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor". Lancet. 341 (8843): 461–2. doi:10.1016/0140-6736(93)90208-X. PMID8094489. S2CID11356360.
Cone RD, Mountjoy KG, Robbins LS, Nadeau JH, Johnson KR, Roselli-Rehfuss L, Mortrud MT (May 1993). "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. Bibcode:1993NYASA.680..342C. doi:10.1111/j.1749-6632.1993.tb19694.x. PMID8390157. S2CID35656702.
Allolio B, Reincke M (1997). "Adrenocorticotropin receptor and adrenal disorders". Hormone Research. 47 (4–6): 273–8. doi:10.1159/000185476. PMID9167964.
Tatro JB (1997). "Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides". Neuroimmunomodulation. 3 (5): 259–84. doi:10.1159/000097281. PMID9218248.
Clark AJ, McLoughlin L, Grossman A (February 1993). "Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor". Lancet. 341 (8843): 461–2. doi:10.1016/0140-6736(93)90208-X. PMID8094489. S2CID11356360.
Naville D, Jaillard C, Barjhoux L, Durand P, Bégeot M (January 1997). "Genomic structure and promoter characterization of the human ACTH receptor gene". Biochemical and Biophysical Research Communications. 230 (1): 7–12. doi:10.1006/bbrc.1996.5911. PMID9020063.
Naville D, Barjhoux L, Jaillard C, Saez JM, Durand P, Bégeot M (April 1997). "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. doi:10.1016/S0303-7207(97)04043-4. PMID9175632. S2CID24112827.
Penhoat A, Naville D, Jaillard C, Durand P, Bégeot M (May 1997). "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. doi:10.1016/S0167-4889(97)00031-1. PMID9194567.
Ishii T, Ogata T, Sasaki G, Sato S, Kinoshita EI, Matsuo N (September 2000). "Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH". Clinical Endocrinology. 53 (3): 389–92. doi:10.1046/j.1365-2265.2000.01040.x. PMID10971458. S2CID418654.
Roy S, Rached M, Gallo-Payet N (July 2007). "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. doi:10.1210/me.2007-0041. PMID17456795.
External links
"Melanocortin Receptors: MC2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-07-23.
