Adrenocorticotropic hormone explained

pro-opiomelanocortin
Width:200px
Hgncid:9201
Symbol:OMC
Entrezgene:5443
Omim:176830
Refseq:NM_000939
Uniprot:P01189
Chromosome:2
Arm:p
Band:23

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 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 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] 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:[4]

polypeptide fragment alias abbreviation amino acid residues
NPP NPP27–102
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.[5] [6] [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.

In human body, total weight ACTH is 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. This effect is observed over several hours.

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.

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.[12]

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.[13] The functional expression of MC2R on the osteoblast was discovered by Isales et alia in 2005.[14] 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.[15] 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

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.[16] [17]

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.[18]

Associated conditions

See also

Notes and References

  1. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms. December 6, 2012. Springer Science & Business Media. 978-94-011-4439-1. 84–.
  2. Dibner C, Schibler U, Albrecht U . The mammalian circadian timing system: organization and coordination of central and peripheral clocks . Annual Review of Physiology . 72 . 517–49 . 2010 . 20148687 . 10.1146/annurev-physiol-021909-135821 .
  3. Web site: Adrenocorticotropic Hormone (ACTH) .
  4. Web site: Pro-opiomelocortin precursor. April 8, 2013.
  5. Yalow RS, Glick SM, Roth J, Berson SA . Radioimmunoassay of human plasma ACTH . The Journal of Clinical Endocrinology and Metabolism . 24 . 11 . 1219–25 . November 1964 . 14230021 . 10.1210/jcem-24-11-1219 .
  6. Book: Patel K . Stability and Characterization of Protein and Peptide Drugs . Stability of Adrenocorticotropic Hormone (ACTH) and Pathways of Deamidation of Asparaginyl Residue in Hexapeptide Segments . Pharmaceutical Biotechnology . 5 . 201–20 . 1993 . 8019694 . 10.1007/978-1-4899-1236-7_6 . 978-1-4899-1238-1 .
  7. Veldhuis JD, Iranmanesh A, Naftolowitz D, Tatham N, Cassidy F, Carroll BJ . Corticotropin secretory dynamics in humans under low glucocorticoid feedback . The Journal of Clinical Endocrinology and Metabolism . 86 . 11 . 5554–63 . November 2001 . 11701735 . 10.1210/jcem.86.11.8046 . free .
  8. https://www.uniprot.org/uniprot/P01189 PROOPIOMELANOCORTIN; NCBI → POMC
  9. Raikhinstein M, Zohar M, Hanukoglu I . cDNA cloning and sequence analysis of the bovine adrenocorticotropic hormone (ACTH) receptor . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1220 . 3 . 329–32 . February 1994 . 8305507 . 10.1016/0167-4889(94)90157-0 .
  10. Hanukoglu I, Feuchtwanger R, Hanukoglu A . Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells . The Journal of Biological Chemistry . 265 . 33 . 20602–8 . November 1990 . 2173715 . 10.1016/S0021-9258(17)30545-8 . free .
  11. Raikhinstein M, Hanukoglu I . 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 . November 1993 . 7504267 . 47806 . 10.1073/pnas.90.22.10509 . 1993PNAS...9010509R . free .
  12. Slominski A, Tobin DJ, Shibahara S, Wortsman J . Melanin pigmentation in mammalian skin and its hormonal regulation . . 84 . 4 . 1155–1228 . 2004 . 10.1152/physrev.00044.2003 . 15383650.
  13. Isales CM, Zaidi M, Blair HC . ACTH is a novel regulator of bone mass . Annals of the New York Academy of Sciences . 1192 . 1 . 110–6 . March 2010 . 20392225 . 10.1111/j.1749-6632.2009.05231.x . 24378203 . 2010NYASA1192..110I .
  14. Zhong Q, Sridhar S, Ruan L, Ding KH, Xie D, Insogna K, Kang B, Xu J, Bollag RJ, Isales CM . 6 . Multiple melanocortin receptors are expressed in bone cells . Bone . 36 . 5 . 820–31 . May 2005 . 15804492 . 10.1016/j.bone.2005.01.020 .
  15. 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 . 6 . 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 . May 2010 . 20421485 . 2889316 . 10.1073/pnas.0912176107 . 2010PNAS..107.8782Z . free .
  16. Johnstone R . A sixty-year evolution of biochemistry at McGill University . Scientia Canadensis . 27 . 27–84 . 2003 . 16116702 . 10.7202/800458ar . free .
  17. Collip JB, Anderson E, Thomson DL . The adrenotropic hormone of the anterior pituitary lobe . . 222 . 5737 . August 12, 1933 . 347–348 . 10.1016/S0140-6736(00)44463-6 .
  18. Simulated ACTH . Time. December 12, 1960 . https://web.archive.org/web/20090906013356/http://www.time.com/time/magazine/article/0,9171,871916,00.html. dead. September 6, 2009.