Chapter 1.5 Molecular biology of the HPA axis

Abstract

Abstract: The hypothalamic-pituitary-adrenal (HPA) axis is a complex endocrine system. Its main role is maintainance of homeostasis following stress. Corticotropin releasing factor (CRF) is the major regulator of the HPA axis, controling the release of pituitary adrenocorticotropin (ACTH). CRF is cosynthesized with vasopressin (AVP) in neurons of the hypothalamic paraventricular nucleus and released into the portal0hypophyseal blood circulation, from whrer it is transported to the anterior pituitary gland. The binding of CRF to its specific receptor (CRF type 1 receptor) on pituitary corticotrophic cells results in stimulation of proopiomelanocortin (POMC) mRNA synthesis and ACTH secretion. ACTH and other biologically active peptides (N-terminal glycopeptide, γ-melanotropin, joining peptide, α-melanotropin, CLIP, β-1ipotropin, β-melanotropin and β-endorphin) are generated by posttranslational cleavage of their precursor peptide POMC. POMC gene transcription is induced by CRF-stimulated elevation in cyclic adenosine 3′,5′-momophosphate (cAMP). Several mediators of CRF-induced POMC regulation and corticotroph differentiation have been identified, such as Nur factors, TPIT, leukaemia-inhibitory factor and interleukin 6. Upon stimulation, ACTH is released into the systemic circulation in a circadian rhythm, orchestrated by the suprachiasmatic nucleus of the hypothalamus. ACTH stimulates steroidogenesis (mineralocorticoids, glucocorticoid and, in humans, adrenal androgens) via the G s -coupled melanocortin 2 receptor (MC2R). ACTH, via cAMP, promotes the synthesis of steroidogenic acute regulatory protein (STAR), which in turn mediates the uptake of cholesterol into the mitochondria of adrenocortical cells. This is followed by coordinated action of cytochrome P 450 enzymes resulting in biosynthesis and secretion of adrenal steroids. Glucocorticoids in particular have wide-ranging effects on many organ systems, as well as a including negative feedback action at the pituitary and hypothalamic level.