Hypothalamic‐Pituitary‐Adrenal Feedback Regulation

Abstract

The hypothalamic‐pituitary‐adrenal axis (HPA) is regulated by corticotrophin‐releasing hormone (CRH), arginine vasopressin (AVP) and by glucocorticoids. In response to stress, the neuroendocrine system releases CRH and AVP to regulate adrenocorticotropin (ACTH) hormone secretion from the anterior pituitary and glucocorticoids from the adrenal cortex. Increasing levels of circulating glucocorticoids downregulate the synthesis of the glucocorticoid receptor (GR) in various tissues in an endocrine feedback loop and produce inhibitory effects on the secretion of CRH and ACTH (4, to bring back the system to its resting state. Despite this wealth of information, the precise mechanism of feedback regulation remains elusive.We have identified FBR sequences in the human GR gene promoter and examined the roles of GR, CREB and HDAC‐6 in the negative feedback regulation associated with promoter elements of the human GR gene. We have demonstrated that the enhancer and suppression activities contained within the promoter elements of the GR gene occur through the interaction of GR and the active recruitment of HDAC‐6 and phosphorylated CREB (CREB‐P) by the ligand bound GR. We demonstrated a direct involvement between GR, CREB and HDAC‐6 in the feedback regulation.In the cortisol depleted state, phosphorylated CREB binds to the CRE in the composite feedback regulatory element and CBP/p/CAF complexes. This interaction results in the acetylation of core histones and chromatin decondensation which turns the GR gene on. In the presence of active glucocorticoids, nGRE recruits GR‐ligand complexes which tether HDAC‐6 and phosphatase complexes. The GR‐DEX bound HDAC‐6 deacetylates core histones and the GR‐DEX tethered phosphatase dephosphorylates CREB‐P. Deacetylation leads to chromatin condensation and dephosphorylation of CREB‐P which results in its removal from the CRE which turns GR gene off.