Adrenocorticotropic hormone

2018-09-13T14:01:22Z

2405:205:2290:C7DD:1FF:F505:613D:EFB7: /* Synthetic ACTH */Making content small

{{Use mdy dates|date=August 2017}}
{{About|adrenocorticotropic hormone as a natural hormone|adrenocorticotropic hormone as a medication and diagnostic agent|Adrenocorticotropic hormone (medication)}}
{{infobox protein
| Name = [[proopiomelanocortin|pro-opiomelanocortin]]
| caption = {{POMC}}
| image =
| width =
| HGNCid = 9201
| Symbol = OMC
| AltSymbols =
| EntrezGene = 5443
| OMIM = 176830
| RefSeq = NM_000939
| UniProt = P01189
| PDB =
| ECnumber =
| Chromosome = 2
| Arm = p
| Band = 23
| LocusSupplementaryData =
}}

'''Adrenocorticotropic hormone''' ('''ACTH''', also '''adrenocorticotropin''', '''corticotropin''') is a [[Peptide|polypeptide]] [[tropic hormone]] produced by and secreted by the [[Anterior pituitary|anterior pituitary gland]].<ref name="MortonHall2012">{{cite book|author1=I.K. Morton|author2=Judith M. Hall|title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA84|date=December 6, 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=84–}}</ref> It is also used as a [[Adrenocorticotropic hormone (medication)|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]] by the [[Adrenal cortex|cortex]] of the [[adrenal gland]]. ACTH is also related to the [[circadian rhythm]] in many organisms.<ref>{{cite journal | vauthors = Dibner C, Schibler U, Albrecht U | title = The mammalian circadian timing system: organization and coordination of central and peripheral clocks | journal = Annual Review of Physiology | volume = 72 | pages = 517–49 | year = 2010 | pmid = 20148687 | doi = 10.1146/annurev-physiol-021909-135821 | postscript = {{inconsistent citations}} }}</ref>

Deficiency of ACTH is a sign 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|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 is the cause of elevated ACTH (from the anterior pituitary) and an excess of cortisol (hypercortisolism) – this constellation of signs and symptoms is known as [[Cushing's syndrome]].

== Production and regulation ==
[[POMC]], ACTH and β-lipotropin are secreted from [[corticotrope]]s in the [[anterior pituitary|anterior lobe]] (or [[adenohypophysis]]) of the [[pituitary gland]] in response to the hormone [[corticotropin-releasing hormone]] (CRH) released by the [[hypothalamus]].<ref>{{cite web |title=Adrenocorticotropic Hormone (ACTH) |url=http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/acth.html}}</ref> ACTH is synthesized from pre-pro-opiomelanocortin (pre-POMC). The removal of the signal [[peptide]] during [[Translation (biology)|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:<ref>{{cite web|title=Pro-opiomelocortin precursor|url=https://www.uniprot.org/uniprot/P01189|accessdate=April 8, 2013}}</ref>
{| class="wikitable"
|-
! polypeptide fragment !! alias !! abbreviation !! amino acid [[residue (chemistry)|residues]]
|-
| 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 (genetics)|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 about ten minutes.<ref name="pmid14230021">{{cite journal | vauthors = Yalow RS, Glick SM, Roth J, Berson SA | title = Radioimmunoassay of human plasma acth | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 24 | issue = 11 | pages = 1219–25 | date = November 1964 | pmid = 14230021 | doi = 10.1210/jcem-24-11-1219 }}</ref>

== Structure ==
ACTH consists of 39 [[amino acid]]s, 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 [[hyperpigmentation|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.

Human ACTH has a molecular weight of 4,540 [[atomic mass unit]]s (Da).<ref>[https://www.uniprot.org/uniprot/P01189 PROOPIOMELANOCORTIN; NCBI --> POMC] Retrieved on September 28, 2009</ref>

== Function ==
ACTH stimulates secretion of [[Glucocorticoid|glucocorticoid steroid hormones]] from adrenal cortex cells, especially in the [[zona fasciculata]] of the adrenal glands. ACTH acts by binding to cell surface [[ACTH receptor]]s, which are located primarily on adrenocortical cells of the [[adrenal cortex]]. The ACTH receptor is a seven-membrane-spanning [[G protein-coupled receptor]].<ref name="pmid8305507">{{cite journal | vauthors = Raikhinstein M, Zohar M, Hanukoglu I | title = cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor | journal = Biochimica et Biophysica Acta | volume = 1220 | issue = 3 | pages = 329–32 | date = February 1994 | pmid = 8305507 | doi = 10.1016/0167-4889(94)90157-0 }}</ref> Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme [[adenylyl cyclase]], which leads to an increase in intracellular [[Cyclic adenosine monophosphate|cAMP]]<ref name="pmid2173715">{{cite journal | vauthors = Hanukoglu I, Feuchtwanger R, Hanukoglu A | title = Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells | journal = The Journal of Biological Chemistry | volume = 265 | issue = 33 | pages = 20602–8 | date = November 1990 | pmid = 2173715 | url = http://www.jbc.org/content/265/33/20602.full.pdf }}</ref> 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.<ref name="pmid2173715" /> This effect is observed over several hours.<ref name="pmid2173715" />

In addition to steroidogenic enzymes, ACTH also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems.<ref name="pmid7504267">{{cite journal | vauthors = Raikhinstein M, Hanukoglu I | title = Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 22 | pages = 10509–13 | date = November 1993 | pmid = 7504267 | pmc = 47806 | doi = 10.1073/pnas.90.22.10509 | bibcode = 1993PNAS...9010509R }}</ref> These actions are probably necessary to supply the enhanced energy needs of adrenocortical cells stimulated by ACTH.<ref name="pmid7504267" />

[[File:Blood values sorted by mass and molar concentration.png|thumb|center|800px|[[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==
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]]. While it has a crucial function in regulating the adrenal, 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.<ref name="pmid20392225">{{cite journal | vauthors = Isales CM, Zaidi M, Blair HC | title = ACTH is a novel regulator of bone mass | journal = Annals of the New York Academy of Sciences | volume = 1192 | issue = | pages = 110–6 | date = March 2010 | pmid = 20392225 | doi = 10.1111/j.1749-6632.2009.05231.x |bibcode = 2010NYASA1192..110I }}</ref> The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005.<ref name="pmid15804492">{{cite journal | vauthors = Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, Kang B, Xu J, Bollag RJ, Isales CM | title = Multiple melanocortin receptors are expressed in bone cells | journal = Bone | volume = 36 | issue = 5 | pages = 820–31 | date = May 2005 | pmid = 15804492 | doi = 10.1016/j.bone.2005.01.020 }}</ref> 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.<ref name="pmid20421485">{{cite journal | vauthors = Zaidi M, Sun L, Robinson LJ, Tourkova IL, Liu L, Wang Y, Zhu LL, Liu X, Li J, Peng Y, Yang G, Shi X, Levine A, Iqbal J, Yaroslavskiy BB, Isales C, Blair HC | title = ACTH protects against glucocorticoid-induced osteonecrosis of bone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 19 | pages = 8782–7 | date = May 2010 | pmid = 20421485 | pmc = 2889316 | doi = 10.1073/pnas.0912176107 |bibcode = 2010PNAS..107.8782Z }}</ref> 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.

== Synthetic ACTH ==
An active synthetic form of ACTH, consisting of the first 24 amino acids of native ACTH, was 1st synthesized by Klaus Hofmann at the [[University of Pittsburgh]].<ref>{{cite news |title=Simulated ACTH |work=[[Time (magazine)|Time]]|date=December 12, 1960 |url=http://www.time.com/time/magazine/article/0,9171,871916,00.html}}</ref>

== Discovery ==
While working on her dissertation, [[Evelyn M. Anderson]] co-discovered ACTH with [[James Collip|James Bertram Collip]] and [[David Landsborough Thomson]] and, in a paper published in 1933, explained its function in the body.<ref>{{cite journal|title=A Sixty-Year Evolution of Biochemistry at McGill University |journal=Scientia Canadensis|volume=27 |date=2003 |pages=27–83|url=http://www.erudit.org/revue/scientia/2003/v27/n/800458ar.pdf|doi=10.7202/800458ar|last1=Johstone|first1=Rose}}</ref><ref>{{cite journal |authors=James B. Collip, Evelyn Anderson, D. L. Thomson |title=The adrenotropic hormone of the anterior pituitary lobe |journal=[[The Lancet|Lancet]] |volume=222 |issue=5737 |date=August 12, 1933 |pages=347–348 |doi=10.1016/S0140-6736(00)44463-6 }}</ref>

== Associated conditions ==
* [[Pituitary disease|Diseases of the pituitary]], the gland that produces, among others, the hormone ACTH
* [[Hypopituitarism]], the hyposecretion of ACTH in the pituitary, leading to secondary [[adrenal insufficiency]] (a form of hypocorticism)
* [[Addison's disease]], the primary adrenal insufficiency (another form of hypocorticism)
* [[Cushing's syndrome]], hypercorticism, one of the causes is hypersecretion of ACTH
* [[Small cell carcinoma]], a common cause of ACTH secreted ectopically
* [[Congenital adrenal hyperplasia]], diseases in the production of cortisol
* [[Nelson's syndrome]], the rapid enlargement of the ACTH producing pituitary after the removal of both adrenal glands
* [[Adrenoleukodystrophy]], can be accompanied by adrenal insufficiency
* [[West syndrome]] ("infantile spasms"), a disease where ACTH is used as a therapy
* [[Postorgasmic illness syndrome]] (POIS), through production of [[tyrosine hydroxylase]] and [[dopamine β-hydroxylase]], which two enzymes comprise the biochemical mechanism by which [[norepinephrine]] and [[epinephrine]] are produced.{{Citation needed|date=August 2015}}

== See also ==
* [[Chromatophobe]]
* [[Corticorelin]]
* [[Dexamethasone suppression test]]

== References ==
{{Reflist}}

== External links ==
* {{MeshName|Adrenocorticotropic+Hormone}}

{{Hormones}}
{{Neuropeptides}}
{{Orexigenics}}
{{Melanocortin receptor modulators}}

{{DEFAULTSORT:Adrenocorticotropic Hormone}}
[[Category:Anterior pituitary hormones]]
[[Category:Peptide hormones]]
[[Category:Melanocortin receptor agonists]]
[[Category:World Anti-Doping Agency prohibited substances]]

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Adrenocorticotropic hormone