Adrenocorticotropic hormone

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
Symbol	OMC
NCBI gene	5443
HGNC	9201
OMIM	176830
RefSeq	NM_000939
UniProt	P01189
Other data
Locus	Chr. 2 p23
Search for Structures Swiss-model Domains InterPro

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 cortex and medulla of the adrenal gland, 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		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. ^{[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. ^[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 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

• 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 ]}
• Critical illness-related corticosteroid insufficiency
• DAVID syndrome, a genetic disorder that is characterized by adrenocorticotropic hormone deficiency combined with common variable immunodeficiency and hypogammaglobulinemia.

See also

• Semax, a synthetic analogue fragment of adrenocorticotropic hormone

References

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.
3. "Adrenocorticotropic Hormone (ACTH)".
4. "Pro-opiomelocortin precursor" . Retrieved April 8, 2013.
5. 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.
6. 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.
7. 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.
8. PROOPIOMELANOCORTIN; NCBI → POMC Retrieved on September 28, 2009
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Johnstone R (2003). "A sixty-year evolution of biochemistry at McGill University" (PDF). Scientia Canadensis. 27: 27–84. doi: 10.7202/800458ar . PMID   16116702.
17. 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.
18. "Simulated ACTH". Time . December 12, 1960. Archived from the original on September 6, 2009.

External links

• Adrenocorticotropic+Hormone at the U.S. National Library of Medicine Medical Subject Headings (MeSH)