Adrenocorticotropic hormone

Adrenocorticotropic hormone

Adrenocorticotropic hormone (ACTH), also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormoneproduced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with corticotropin-releasing hormone from the hypothalamus). Its principal effects are increased production and release of corticosteroids and, as its name suggests, cortisol from the adrenal cortex.

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 glycosylationbefore it is proteolytically cleaved by endopeptidases to yield various polypeptide fragments with varying physiological activity. These fragments include NPP, Melanotropin Gamma (γ-MSH), Potential Peptide, Corticotropin (Adrenocorticotropic Hormone, or ACTH), Melanotropin Alpha (Melanocyte-Stimulating Hormone, or α-MSH), Corticotropin-like Intermediate Peptide (CLIP), Lipotropin Beta (β-LPH), Lipotropin Gamma (γ-LPH), Melanotropin Beta (β-MSH), Beta-Endorphin, and Met-Enkephalin. 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.^[1]

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.

ACTH is also related to the circadian rhythm in many organisms. The half-life of ACTH in human blood is about ten minutes.

[edit]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).^[2]

[edit]Function

ACTH acts through the stimulation of cell surface ACTH receptors, which are located primarily on adrenocortical cells of the adrenal cortex. This results in the synthesis and secretion of gluco- and mineralo-corticosteroids and androgenic steroids. The ACTH receptor is a seven-membrane-spanning G protein-coupled receptor. Upon ligand binding, the receptor undergoes conformation changes that stimulate the enzyme adenylyl cyclase, which leads to an increase in intracellular cAMP and subsequent activation of protein kinase A. This ultimately results in stimulation of steroidogenesis.

ACTH acts at several key steps to influence the steroidogenic pathway in the adrenal cortex:

§ ACTH stimulates lipoprotein uptake into cortical cells. This increases the bio-availability of cholesterol in the cells of the adrenal cortex.

§ ACTH increases the transport of cholesterol into the mitochondria and activates its hydrolysis.

§ ACTH Stimulates cholesterol side-chain cleavage enzyme, which makes the rate-limiting step in steroidogenesis.^[3] This results in the production of pregnenolone.

Synthetic ACTH

An active synthetic form of ACTH, consisting of the first 23 amino acids of native ACTH, was first synthesized by Klaus Hofmann at the University of Pittsburgh.^[4] ACTH is available as a synthetic derivative in the forms of cosyntropin, tradename Cortrosyn, and synacthen (synthetic ACTH). Both are very rarely used in place of glucocorticoids to treat secondary adrenal insufficiency in a hospital setting, but are used primarily 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 $47,000.