Schematic representation of the key mechanisms in HPA-axis glucocorticoid-mediated feedback actions. Two membrane receptors (GPCR, CRHR) mediate extracellular concentrations of cortisol and CRH, inhibiting and stimulating the secretion of ACTH, respectively. In response to a variety of external stressors, CRH is released from the hypothalamus and stimulates the anterior pituitary via CRH-receptors (CRHR) to immediately secrete ACTH, which in turn stimulates the adrenal cortex to synthesize and release cortisol. Thereby non-genomic signaling mechanisms mediate tethering and fusion of ACTH vesicles to the plasma membrane of corticotrophic cells and the fast secretion of ACTH molecules into the extracellular space within minutes after CRH administration. Whereas G-protein-coupled receptors (GPCR) are thought to mediate fast negative feedback actions of glucocorticoids (e.g., cortisol) which downregulate (CRH-induced) ACTH secretion in the anterior pituitary gland. The cytoplasmic organelles such as endoplasmic reticulum, Golgi apparatus, or vesicles are neglected for simplicity.