Chronically elevated circulating glucocorticoid levels are although to enhance vulnerability to psychopathology. Here we hypothesized that such sustained glucocorticoid levels, disturbing corticosterone pulsatility, attenuate glucocorticoid receptor signaling and target gene responsiveness to an acute challenge in the rat brain. Rats were implanted with vehicle or 40 or 100% corticosterone pellets known to flatten ultradian and circadian rhythmicity while maintaining daily average levels or mimic pathological conditions. Additionally, recovery from constant exposure was studied in groups that had the pellet removed 24 h prior to the challenge. Molecular markers for receptor responsiveness (receptor levels, nuclear translocation, promoter occupancy, and target gene expression) to an acute challenge mimicking the stress response (3 mg/kg ip) were studied in the hippocampal area. Implantation of 40 and 100% corticosterone pellets dose-dependently down-regulated glucocorticoid receptor and attenuated mineralocorticoid receptor and glucocorticoid receptor translocation to the acute challenge. Interestingly, whereas target gene Gilz expression to the challenge was already attenuated by tonic daily average levels (40%), Sgk-1 was affected only after constant high corticosterone exposure (100%), indicating altered receptor responsiveness due to treatment. Washout of 100% corticosterone recovered all molecular markers (partial), whereas removal of the 40% corticosterone pellet still attenuated responsiveness to the challenge. We propose that corticosteroid pulsatility is crucial in maintaining normal responsiveness to glucocorticoids. Whereas the results with 100% corticosterone are likely attributed to receptor saturation, subtle changes in the pattern of exposure (40%) induces changes at least as severe for glucocorticoid signaling as overt hypercorticism, suggesting an underlying mechanism sensitive to the pattern of hormone exposure.

Protection against injurious external insults and loss of vital fluids is essential for life and is in all organisms, from bacteria to plants and humans, provided by some form of barrier. Members of the small proline-rich (SPRR) protein family are major components of the cornified cell envelope (CE), a structure responsible for the barrier properties of our skin. These proteins are efficient reactive oxygen species (ROS) quenchers involved not only in the establishment of the skin's barrier function but also in cell migration and wound healing. Here, a proteomic analysis of in vivo SPRR-interacting proteins confirmed their function in CE-formation and ROS-quenching and also revealed a novel unexpected role in DNA-binding. Direct in vitro and in vivo evidence proved that the DNA-binding capacity of SPRRs is regulated by the oxidation state of the proteins. At low ROS levels, nuclear SPRR is able to bind DNA and prevent ROS-induced DNA damage. When ROS levels increase, SPRR proteins multimerize and form an effective antioxidant barrier at the cell periphery, possibly to prevent the production or infiltration of ROS. At even higher ROS exposure, DNA-binding is restituted. A molecular model explaining how the intracellular oxidation state of SPRRs likely influences their selective protective function is provided.