Chapter 3 - Adrenocorticotrophin

Abstract

Adrenocorticotrophin (ACTH) is the anterior pituitary mediator of the hypothalamic–pituitary–adrenal axis that regulates responses to a variety of stressors, including 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 several 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. In response to ultraviolet light exposure, skin α-MSH is released and binds to MC1R, which stimulates 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 hypothalamic paraventricular nuclei 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. MC2R and MC4R require an accessory protein for their functions, melanocortin receptor 2 accessory protein (MRAP), and MRAP2, respectively, and mutations in these proteins impair associated receptor function.