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Adrenocorticotropic hormone

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(Redirected fromACTH)
This article is about adrenocorticotropic hormone as a natural hormone. For adrenocorticotropic hormone as a medication and diagnostic agent, seeAdrenocorticotropic hormone (medication).

pro-opiomelanocortin
Identifiers
SymbolOMC
NCBI gene5443
HGNC9201
OMIM176830
RefSeqNM_000939
UniProtP01189
Other data
LocusChr. 2p23
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;alsoadrenocorticotropin,corticotropin) is apolypeptidetropic hormoneproduced by and secreted by theanterior pituitary gland.[1]It is also used as amedication and diagnostic agent.ACTH is an important component of thehypothalamic-pituitary-adrenal axisand is often produced in response to biological stress (along with its precursorcorticotropin-releasing hormonefrom thehypothalamus). Its principal effects are increased production and release ofcortisoland androgens by the zona fasiculata and zona reticularis, respectively. ACTH is also related to thecircadian rhythmin many organisms.[2]

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

Production and regulation

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POMC,ACTH and β-lipotropin are secreted fromcorticotropic cellsin theanterior lobe(oradenohypophysis) of thepituitary glandin response to the hormonecorticotropin-releasing hormone(CRH) released by thehypothalamus.[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 signalpeptideduringtranslationproduces the 241-amino acidpolypeptidePOMC, which undergoes a series ofpost-translational modificationssuch asphosphorylationandglycosylationbefore it is proteolytically cleaved byendopeptidasesto yield various polypeptide fragments with varying physiological activity. These fragments include:[5]

polypeptide fragment alias abbreviation amino acidresidues
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.Glucocorticoidssecreted 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 genetranscriptionand 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.

Thehalf-lifeof ACTH in human blood is reported to be between ten and 30 minutes.[6][7][8]

Structure

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ACTH consists of 39amino acids,the first 13 of which (counting from the N-terminus) may be cleaved to formα-melanocyte-stimulating hormone(α-MSH) (this common structure is responsible forexcessively tanned skinin 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 4,540atomic mass units(Da).[9]

Function

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ACTH stimulates secretion ofglucocorticoid steroid hormonesfrom adrenal cortex cells, especially in thezona fasciculataof the adrenal glands. ACTH acts by binding to cell surfaceACTH receptors,which are located primarily on adrenocortical cells of theadrenal cortex.The ACTH receptor is a seven-membrane-spanningG protein-coupled receptor.[10]Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzymeadenylyl cyclase,which leads to an increase in intracellularcAMP[11]and subsequent activation ofprotein 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 theP450sccenzyme is located. P450scc catalyzes the first step of steroidogenesis that is cleavage of the side-chain of cholesterol. ACTH also stimulateslipoproteinuptake into cortical cells. This increases thebioavailabilityofcholesterolin 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 includingα-MSHthat stimulates the production ofmelanin.A family of related receptors mediates the actions of these hormones, the MCR, ormelanocortin receptorfamily. These are mainly not associated with thepituitary-adrenalaxis. MC2R is theACTH receptor.[13]

While it has a crucial function in regulating the adrenal glands, it is also expressed elsewhere in the body, specifically in theosteoblast,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 ofVEGF,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. Andersonco-discovered ACTH withJames Bertram CollipandDavid Landsborough Thomsonand, 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 theUniversity 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–.ISBN978-94-011-4439-1.
  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.PMID20148687.Archived(PDF)from the original on April 4, 2023.RetrievedJune 28,2019.
  3. ^"Adrenocorticotropic Hormone (ACTH)".vivo.colostate.edu.Archived fromthe originalon May 22, 2023.RetrievedOctober 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.PMID38343101.
  5. ^"Pro-opiomelocortin precursor".UniProt.Archivedfrom the original on July 16, 2024.RetrievedApril 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.PMID14230021.
  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.ISBN978-1-4899-1238-1.PMID8019694.
  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.PMID11701735.
  9. ^PROOPIOMELANOCORTIN; NCBI → POMCArchivedJuly 16, 2024, at theWayback MachineRetrieved 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.PMID8305507.Archivedfrom the original on September 13, 2017.RetrievedJune 28,2019.
  11. ^abcHanukoglu 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.PMID2173715.Archived(PDF)from the original on September 16, 2012.RetrievedJuly 24,2012.
  12. ^abRaikhinstein 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.PMC47806.PMID7504267.
  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.PMID15383650.
  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.PMID20392225.S2CID24378203.
  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.PMID15804492.
  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.PMC2889316.PMID20421485.
  17. ^Johnstone R (2003)."A sixty-year evolution of biochemistry at McGill University"(PDF).Scientia Canadensis.27:27–84.doi:10.7202/800458ar.PMID16116702.Archived(PDF)from the original on November 17, 2015.RetrievedNovember 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 fromthe originalon September 6, 2009.
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