Control of the CRF system exists at multiple levels to ensure rapid and specific hormone release that is followed by appropriate restoration to steady state. Glucocorticoids, the final product of HPA activation, impose a vital form of negative regulation on HPA activity. Biosynthesis and secretion of CRF in the PVN and ACTH in the anterior pituitary are suppressed directly by glucocorticoids. In addition, glucocorticoid-mediated negative feedback occurs at the level of the hippocampus, which sends projections via the BNST to inhibit CRF activity in the PVN. Thus, glucocorticoids provide an essential means of terminating HPA axis activation (de Kloet et al., 1998). In addition to this critical form of negative feedback, glucocorticoids provide a positive influence on CRF whereby they increase CRF mRNA expression and CRF content in the central amygdala and BNST (Makino et al., 1994; Cook, 2002). Such elevations in limbic CRF activity likely potentiate anticipatory behaviors such as anxiety and fear. Thus, glucocorticoids refine the response to stress, differentially modulating hypothalamic and amygdaloid CRF systems to dampen HPA axis activity while enhancing behavioral adjustments to stress (Schulkin et al., 1998).
Glucocorticoid actions are mediated by two closely related intracellular receptors, mineralocorti-coid receptors (MR) and glucocorticoid receptors (GR) (reviewed in (de Kloet et al., 1998)). GR are broadly expressed in most cell types while MR show a restricted expression pattern confined to brain, kidney, colon, and exocrine glands. In brain, MR are found in neurons of the septum, amygdala, and hippocampus while key sites of GR expression include the hippocampus, PVN, and anterior pituitary corticotropes. Evidence to date suggests that hippocampal MR mediates tonic influences of glucocorticoids whereas GR occupancy stimulates negative feedback regulatory actions (Reul and de Kloet, 1985; de Kloet and Reul, 1987). These receptors are ligand-regulated transcription factors within the nuclear hormone receptor superfamily that control the transcription rate of target genes. Activation or repression of gene transcription occurs via homodimer binding of GR to glucocorticoid responsive elements in DNA promoter regions. In addition, it has been shown that GR regulate transcription by interfering with functions of other transcription factors (e.g., activating protein 1 and nuclear factor-KB) via protein-protein interactions. Thus, multiple interactions at the DNA and protein level provide diversity and complexity of transcriptional control by glucocorticoids.
The CRF system is also regulated by the CRF-binding protein (CRF-BP), a 37-kD glycoprotein, which binds CRF and urocortin 1 with high affinity (Behan et al., 1989). Urocortins 2 and 3 do not show appreciable binding. CRF-BP is believed to regulate CRF/urocortin actions in vivo by reducing available CRF/urocortin levels. In vitro, CRF-BP has been shown to antagonize CRF-induced secretion of ACTH from pituitary cells (Linton et al., 1990; Cortright et al., 1995). Furthermore, several sites of CRF-BP expression colocalize with CRF neurons (e.g., central nucleus of the amygdala, and lateral septal nucleus), or CRF target cells, most notably pituitary corticotropes (Potter et al., 1992). It has been reported that CRF-BP binds 40-90% of total CRF, thus the availability of "free CRF" may be determined, in large part, by CRF-BP (Behan et al., 1997).
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