Chapter 3 - Adrenocorticotrophin

Abstract

Adrenocorticotrophin (ACTH) is the anterior pituitary mediator of the hypothalamic–pituitary–adrenal axis that regulates the body's responses to a variety of stressors, particularly hypoglycemia, psychological stressors such as fear, and physical stressors such as hypovolemia. ACTH is the 39 amino acid product of proopiomelanocortin (POMC), which is principally synthesized in anterior pituitary corticotrophs, neurons of the mediobasal hypothalamus, and skin melanocytes. In each of these cell types, POMC is processed to a variety of melanocortins: ACTH (in the pituitary), α-MSH (in the skin and hypothalamus), and β-endorphin (in all three). ACTH, in response to hypothalamic corticotrophin–releasing hormone, is secreted and binds to the adrenal melanocortin 2 receptor (MC2R), a G protein–coupled receptor that signals through cyclic AMP to stimulate cortisol production and secretion. The main action of cortisol is to maintain adequate body fuel supplies and blood pressure during times of stress. α-MSH in skin, in response to ultraviolet light exposure, is released and binds to MC1R, which stimulates the production of melanin to increase skin pigmentation. α-MSH in the hypothalamus, in response to leptin, is released from neurons to act through MC4R receptors in the paraventricular nucleus of the hypothalamus, to decrease appetite and increase energy expenditure. Diseases involving ACTH are due to pituitary or ectopic tumors that secrete excessive ACTH, faulty transcription of the POMC gene, abnormal cleavage of the POMC precursor, or defects in signaling of POMC products via (at least) MC1R, MC2R, or MC4R. In addition, MC2R and MC4R require an accessory protein for their function, namely, melanocortin receptor 2 accessory protein (MRAP), and MRAP2, respectively, and mutations in these proteins impair the function of their associated receptors.