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Adrenocorticotropic hormone

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(Redirected from Corticotrophin)
This article is about adrenocorticotropic hormone as a natural hormone. For adrenocorticotropic hormone as a medication and diagnostic agent, see Adrenocorticotropic hormone (medication).

pro-opiomelanocortin
Identifiers
SymbolOMC
NCBI gene5443
HGNC9201
OMIM176830
RefSeqNM_000939
UniProtP01189
Other data
LocusChr. 2 p23
Search for
StructuresSwiss-model
DomainsInterPro
proopiomelanocortin derivatives
POMC
     
γ-MSH ACTH β-lipotropin
         
  α-MSH CLIP γ-lipotropin β-endorphin
       
    β-MSH  

Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland.[1] It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with its precursor corticotropin-releasing hormone from the hypothalamus). Its principal effects are increased production and release of cortisol and androgens by the zona fasiculata and zona reticularis, respectively. ACTH is also related to the circadian rhythm in many organisms.[2]

Deficiency of ACTH is an indicator of secondary adrenal insufficiency (suppressed production of ACTH due to an impairment of the pituitary gland or hypothalamus, cf. hypopituitarism) or tertiary adrenal insufficiency (disease of the hypothalamus, with a decrease in the release of corticotropin releasing hormone (CRH)). Conversely, chronically elevated ACTH levels occur in primary adrenal insufficiency (e.g. Addison's disease) when adrenal gland production of cortisol is chronically deficient. In Cushing's disease, a pituitary tumor leads to excessive production of ACTH, which stimulates the adrenal cortex to produce high levels of cortisol.

Production and regulation

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POMC, ACTH and β-lipotropin are secreted from corticotropic cells in the anterior lobe (or adenohypophysis) of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus.[3] The pre-pro-opiomelanocortin (Pre-POMC) is the precursor of POMC, its cleavage forms POMC.[4] ACTH, on the other hand, is produced from the cleavage of POMC. The removal of the signal peptide during translation produces the 241-amino acid polypeptide POMC, which undergoes a series of post-translational modifications such as phosphorylation and glycosylation before it is proteolytically cleaved by endopeptidases to yield various polypeptide fragments with varying physiological activity. These fragments include:[5]

polypeptide fragment alias abbreviation amino acid residues
NPP NPP 27–102
melanotropin gamma γ-MSH 77–87
potential peptide 105–134
corticotropin adrenocorticotropic hormone ACTH 138–176
melanotropin alpha melanocyte-stimulating hormone α-MSH 138–150
corticotropin-like intermediate peptide CLIP 156–176
lipotropin beta β-LPH 179–267
lipotropin gamma γ-LPH 179–234
melanotropin beta β-MSH 217–234
beta-endorphin 237–267
met-enkephalin 237–241

In order to regulate the secretion of ACTH, many substances secreted within this axis exhibit slow/intermediate and fast feedback-loop activity. Glucocorticoids secreted from the adrenal cortex work to inhibit CRH secretion by the hypothalamus, which in turn decreases anterior pituitary secretion of ACTH. Glucocorticoids may also inhibit the rates of POMC gene transcription and peptide synthesis. The latter is an example of a slow feedback loop, which works on the order of hours to days, whereas the former works on the order of minutes.

The half-life of ACTH in human blood is reported to be between ten and 30 minutes.[6][7][8]

Structure

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ACTH consists of 39 amino acids, the first 13 of which (counting from the N-terminus) may be cleaved to form α-melanocyte-stimulating hormone (α-MSH) (this common structure is responsible for excessively tanned skin in Addison's disease). After a short period of time, ACTH is cleaved into α-melanocyte-stimulating hormone (α-MSH) and CLIP, a peptide with unknown activity in humans.

In human body, total weight ACTH is 4,540 atomic mass units (Da).[9]

Function

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ACTH stimulates secretion of glucocorticoid steroid hormones from adrenal cortex cells, especially in the zona fasciculata of the adrenal glands. ACTH acts by binding to cell surface ACTH receptors, which are located primarily on adrenocortical cells of the adrenal cortex. The ACTH receptor is a seven-membrane-spanning G protein-coupled receptor.[10] Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP[11] and subsequent activation of protein kinase A.

ACTH influences steroid hormone secretion by both rapid short-term mechanisms that take place within minutes and slower long-term actions. The rapid actions of ACTH include stimulation of cholesterol delivery to the mitochondria where the P450scc enzyme is located. P450scc catalyzes the first step of steroidogenesis that is cleavage of the side-chain of cholesterol. ACTH also stimulates lipoprotein uptake into cortical cells. This increases the bioavailability of cholesterol in the cells of the adrenal cortex.

The long term actions of ACTH include stimulation of the transcription of the genes coding for steroidogenic enzymes, especially P450scc, steroid 11β-hydroxylase, and their associated electron transfer proteins.[11] This effect is observed over several hours.[11]

In addition to steroidogenic enzymes, ACTH also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems.[12] These actions are probably necessary to supply the enhanced energy needs of adrenocortical cells stimulated by ACTH.[12]

Reference ranges for blood tests, showing adrenocorticotropic hormone (green at left) among the hormones with smallest concentration in the blood

ACTH receptors outside the adrenal gland

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As indicated above, ACTH is a cleavage product of the pro-hormone, proopiomelanocortin (POMC), which also produces other hormones including α-MSH that stimulates the production of melanin. A family of related receptors mediates the actions of these hormones, the MCR, or melanocortin receptor family. These are mainly not associated with the pituitary-adrenal axis. MC2R is the ACTH receptor.[13]

While it has a crucial function in regulating the adrenal glands, it is also expressed elsewhere in the body, specifically in the osteoblast, which is responsible for making new bone, a continual and highly regulated process in the bodies of air-breathing vertebrates.[14] The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005.[15] Since that time, it has been demonstrated that the response of bone forming cells to ACTH includes production of VEGF, as it does in the adrenal. This response might be important in maintaining osteoblast survival under some conditions.[16] If this is physiologically important, it probably functions in conditions with short-period or intermittent ACTH signaling, since with continual exposure of osteoblasts to ACTH, the effect was lost in a few hours.

History

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While working on her dissertation, Evelyn M. Anderson co-discovered ACTH with James Bertram Collip and David Landsborough Thomson and, in a paper published in 1933, explained its function in the body.[17][18]

An active synthetic form of ACTH, consisting of the first 23 amino acids of native ACTH, was first made by Klaus Hofmann at the University of Pittsburgh.[19]

Associated conditions

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See also

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References

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  1. ^ Morton IK, Hall JM (December 6, 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 84–. ISBN 978-94-011-4439-1.
  2. ^ Dibner C, Schibler U, Albrecht U (2010). "The mammalian circadian timing system: organization and coordination of central and peripheral clocks" (PDF). Annual Review of Physiology. 72: 517–49. doi:10.1146/annurev-physiol-021909-135821. PMID 20148687. Archived (PDF) from the original on April 4, 2023. Retrieved June 28, 2019.
  3. ^ "Adrenocorticotropic Hormone (ACTH)". vivo.colostate.edu. Archived from the original on May 22, 2023. Retrieved October 15, 2008.
  4. ^ Chen, Xuanyu (February 11, 2024). "An analysis of POMC gene methylation and expression in patients with schizophrenia". International Journal of Developmental Neuroscience. 84 (3). Wiley: 208–216. doi:10.1002/jdn.10319. PMID 38343101.
  5. ^ "Pro-opiomelocortin precursor". UniProt. Archived from the original on July 16, 2024. Retrieved April 8, 2013.
  6. ^ Yalow RS, Glick SM, Roth J, Berson SA (November 1964). "Radioimmunoassay of human plasma ACTH". The Journal of Clinical Endocrinology and Metabolism. 24 (11): 1219–25. doi:10.1210/jcem-24-11-1219. PMID 14230021.
  7. ^ Patel K (1993). "Stability of Adrenocorticotropic Hormone (ACTH) and Pathways of Deamidation of Asparaginyl Residue in Hexapeptide Segments". Stability and Characterization of Protein and Peptide Drugs. Pharmaceutical Biotechnology. Vol. 5. pp. 201–20. doi:10.1007/978-1-4899-1236-7_6. ISBN 978-1-4899-1238-1. PMID 8019694.
  8. ^ Veldhuis JD, Iranmanesh A, Naftolowitz D, Tatham N, Cassidy F, Carroll BJ (November 2001). "Corticotropin secretory dynamics in humans under low glucocorticoid feedback". The Journal of Clinical Endocrinology and Metabolism. 86 (11): 5554–63. doi:10.1210/jcem.86.11.8046. PMID 11701735.
  9. ^ PROOPIOMELANOCORTIN; NCBI → POMC Archived July 16, 2024, at the Wayback Machine Retrieved on September 28, 2009
  10. ^ Raikhinstein M, Zohar M, Hanukoglu I (February 1994). "cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1220 (3): 329–32. doi:10.1016/0167-4889(94)90157-0. PMID 8305507. Archived from the original on September 13, 2017. Retrieved June 28, 2019.
  11. ^ a b c Hanukoglu I, Feuchtwanger R, Hanukoglu A (November 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells" (PDF). The Journal of Biological Chemistry. 265 (33): 20602–8. doi:10.1016/S0021-9258(17)30545-8. PMID 2173715. Archived (PDF) from the original on September 16, 2012. Retrieved July 24, 2012.
  12. ^ a b Raikhinstein M, Hanukoglu I (November 1993). "Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells". Proceedings of the National Academy of Sciences of the United States of America. 90 (22): 10509–13. Bibcode:1993PNAS...9010509R. doi:10.1073/pnas.90.22.10509. PMC 47806. PMID 7504267.
  13. ^ Slominski A, Tobin DJ, Shibahara S, Wortsman J (2004). "Melanin pigmentation in mammalian skin and its hormonal regulation". Physiological Reviews. 84 (4): 1155–1228. doi:10.1152/physrev.00044.2003. PMID 15383650.
  14. ^ Isales CM, Zaidi M, Blair HC (March 2010). "ACTH is a novel regulator of bone mass". Annals of the New York Academy of Sciences. 1192 (1): 110–6. Bibcode:2010NYASA1192..110I. doi:10.1111/j.1749-6632.2009.05231.x. PMID 20392225. S2CID 24378203.
  15. ^ Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, et al. (May 2005). "Multiple melanocortin receptors are expressed in bone cells". Bone. 36 (5): 820–31. doi:10.1016/j.bone.2005.01.020. PMID 15804492.
  16. ^ Zaidi M, Sun L, Robinson LJ, Tourkova IL, Liu L, Wang Y, et al. (May 2010). "ACTH protects against glucocorticoid-induced osteonecrosis of bone". Proceedings of the National Academy of Sciences of the United States of America. 107 (19): 8782–7. Bibcode:2010PNAS..107.8782Z. doi:10.1073/pnas.0912176107. PMC 2889316. PMID 20421485.
  17. ^ Johnstone R (2003). "A sixty-year evolution of biochemistry at McGill University" (PDF). Scientia Canadensis. 27: 27–84. doi:10.7202/800458ar. PMID 16116702. Archived (PDF) from the original on November 17, 2015. Retrieved November 16, 2015.
  18. ^ Collip JB, Anderson E, Thomson DL (August 12, 1933). "The adrenotropic hormone of the anterior pituitary lobe". Lancet. 222 (5737): 347–348. doi:10.1016/S0140-6736(00)44463-6.
  19. ^ "Simulated ACTH". Time. December 12, 1960. Archived from the original on September 6, 2009.
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