Adrenocorticotropic hormone


Source: http://en.wikipedia.org/wiki/Adrenocorticotropic_hormone
Updated: 2015-05-26T12:48Z
pro-opiomelanocortin
Identifiers
SymbolOMC
Entrez5443
HUGO9201
OMIM176830
RefSeqNM_000939
UniProtP01189
Other data
LocusChr. 2p23

Adrenocorticotropic hormone (ACTH), also known as corticotropin (INN, BAN) (brand names Acortan, ACTH, Acthar, Acton, Cortigel, Trofocortina),[1][2] is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland.[3] It 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. Primary adrenal insufficiency, also called Addison's disease, occurs when adrenal gland production of cortisol is chronically deficient, resulting in chronically elevated ACTH levels; when a pituitary tumor is the cause of elevated ACTH (from the anterior pituitary) this is known as Cushing's disease and the constellation of signs and symptoms of the excess cortisol (hypercortisolism) is known as Cushing's syndrome. A deficiency of ACTH is a cause of secondary adrenal insufficiency. ACTH is also related to the circadian rhythm in many organisms.[4]

In addition to its endogenous role, ACTH is used clinically as a diagnostic agent in assessing adrenal function.[1][2][3]

Production and regulation

POMC, ACTH and β-lipotropin are secreted from corticotropes in the anterior lobe (or adenohypophysis) of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus.[5] ACTH is synthesized from pre-pro-opiomelanocortin (pre-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:[6]

polypeptide fragmentaliasabbreviationamino acid residues
NPP27–102
melanotropin gammaγ-MSH77–87
potential peptide105–134
corticotropinadrenocorticotropic hormoneACTH138–176
melanotropin alphamelanocyte-stimulating hormoneα-MSH138–150
corticotropin-like intermediate peptideCLIP156–176
lipotropin betaβ-LPH179–267
lipotropin gammaγ-LPH179–234
melanotropin betaβ-MSH217–234
beta-endorphin237–267
met-enkephalin237–241

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 about ten minutes.[7]

Structure

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.

Human ACTH has a molecular weight of 4,540 atomic mass units (Da).[8]

Function

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.[9] Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP[10] 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.[10] This effect is observed over several hours.[10]

In addition to steroidogenic enzymes, ACTH also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems.[11] These actions are probably necessary to supply the enhanced energy needs of adrenocortical cells stimulated by ACTH.[11]

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

ACTH receptors outside of 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.[12] The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005.[13] 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.[14] 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 first synthesized by Klaus Hofmann at the University of Pittsburgh.[15] ACTH is available as a synthetic derivative in the forms of cosyntropin, tradename Cortrosyn, and Synacthen (synthetic ACTH). Synacthen is not FDA approved but is used in the UK and Australia to conduct the ACTH stimulation test.

ACTH was first synthesized as a replacement for Acthar Gel, a long-lasting animal product used to treat infantile spasms. Once relatively inexpensive, Acthar Gel is currently an extremely expensive pharmaceutical product. Prices per vial have been as high as $36,000.[16][17] Acthar gel has been proposed as a therapy to treat refractory autoimmune diseases[16] and refractory nephrotic syndrome due to a variety of glomerular diseases.[18]

Associated conditions

See also

References

  1. ^ a bIndex Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 275–. ISBN 978-3-88763-075-1. 
  2. ^ a bJ. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 316–. ISBN 978-1-4757-2085-3. 
  3. ^ a bI.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 84–. ISBN 978-94-011-4439-1. 
  4. ^Dibner C, Schibler U, Albrecht U (2010). "The mammalian circadian timing system: organization and coordination of central and peripheral clocks". Annual Review of Physiology72: 517–49. PMID 20148687. doi:10.1146/annurev-physiol-021909-135821 
  5. ^"Adrenocorticotropic Hormone (ACTH)". 
  6. ^"Pro-opiomelocortin precursor". Retrieved 8 April 2013. 
  7. ^Yalow RS, Glick SM, Roth J, Berson SA (Nov 1964). "RADIOIMMUNOASSAY OF HUMAN PLASMA ACTH". The Journal of Clinical Endocrinology and Metabolism24 (11): 1219–25. PMID 14230021. doi:10.1210/jcem-24-11-1219. 
  8. ^PROOPIOMELANOCORTIN; NCBI --> POMC Retrieved on September 28, 2009
  9. ^Raikhinstein M, Zohar M, Hanukoglu I (Feb 1994). "cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor". Biochimica Et Biophysica Acta1220 (3): 329–32. PMID 8305507. doi:10.1016/0167-4889(94)90157-0. 
  10. ^ a b cHanukoglu I, Feuchtwanger R, Hanukoglu A (Nov 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells"(PDF). The Journal of Biological Chemistry265 (33): 20602–8. PMID 2173715. 
  11. ^ a bRaikhinstein M, Hanukoglu I (Nov 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 America90 (22): 10509–13. Bibcode:1993PNAS...9010509R. PMC 47806. PMID 7504267. doi:10.1073/pnas.90.22.10509. 
  12. ^Isales CM, Zaidi M, Blair HC (Mar 2010). "ACTH is a novel regulator of bone mass". Annals of the New York Academy of Sciences1192: 110–6. PMID 20392225. doi:10.1111/j.1749-6632.2009.05231.x. 
  13. ^Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K et al. (May 2005). "Multiple melanocortin receptors are expressed in bone cells". Bone36 (5): 820–31. PMID 15804492. doi:10.1016/j.bone.2005.01.020. 
  14. ^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 America107 (19): 8782–7. PMC 2889316. PMID 20421485. doi:10.1073/pnas.0912176107. 
  15. ^"Simulated ACTH". Time. December 12, 1960. 
  16. ^ a bGettig J, Cummings JP, Matuszewski K (May 2009). "H.p. Acthar gel and cosyntropin review: clinical and financial implications". P & T34 (5): 250–7. PMC 2697107. PMID 19561871. 
  17. ^Pollack A (2012-12-29). "Questcor Finds Profits, at $28,000 a Vial". New York Times. 
  18. ^Bomback AS, Tumlin JA, Baranski J, Bourdeau JE, Besarab A, Appel AS et al. (2011). "Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel". Drug Design, Development and Therapy5: 147–53. PMC 3063118. PMID 21448451. doi:10.2147/DDDT.S17521. 

External links

Recommended for you