Adrenocorticosteroid receptors such as the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), are primarily localized in the cytoplasm of target cells in association with the 90-kDa heat-shock protein, hsp90. After the discovery of receptor binding to hsp90, it was thought that dissociation of hsp90 from the steroid receptors may account for loss of steroid-binding activity as well as acquisition of DNA-binding activity. Today we know that such association with the hsp90-based chaperone system is a sine qua non  requirement for corticosteroid receptors to acquire a steroid binding conformation, as well as to repress transcriptional activity. Upon steroid binding, cytoplasmic receptors must translocate into the nucleus and bind to cognate DNA-binding sequences to trigger a biological response. Along this pathway, corticosteroid receptors undergo phosphorylation and/or dephosphorylation. It is thought that these processes may regulate not only the transactivational activity of these receptors at the nuclear level, but also the translocation of the steroid/receptor complex into the nucleus. In effect, there is experimental evidence which shows that inhibitors of certain protein phosphatases impair the nuclear translocation of both corticosteroid receptors, although  there are  specific  differences between them. Thus, the steroid-dependent MR nuclear translocation appears to be directly inhibited by serine/threonine phosphatase inhibitors, whereas the translocation of the GR is triggered by hormone regardless of whether or not the inhibitors are present. However, when the nuclear GR cycles back to the  cytoplasm upon hormone withdrawn in the presence of the phosphatase inhibitor, the nuclear translocation can be now impaired upon further reincubation with steroid. This inhibition is abolished if the cytoskeleton is disrupted with colcemid and, surprisingly, the GR is recovered in the nucleus still associated with hsp90 before the receptor binds to chromatin.

An additional variable that also exhibits dramatic effects on the normal function of the steroid receptors is the redox potential of the cell. It has been well established that, like most of the other members of the steroid receptor superfamily, both the MR and the GR possess cysteine groups which are essential for ligand binding and, consequently, to initiate the specific biological response. Nevertheless, a differential sensitivity to the redox milieu is observed for both receptors. While the MR is extremely sensitive to a low redox potential medium, the GR requires more drastic oxidative conditions to abrogate its function. Despite the high structural homology exhibited by both proteins, one of the apparently differential features between them seems to be that those essential amino acid groups are more protrusive in the MR than in the GR. In vivo depletion of glutathione, the most abundant reducing thiol agent in the cells, leads to a diminished mineralocorticoid biological response upon stimulation with aldosterone. Accordingly, the steroid binding capacity is also inhibited. On the other hand, the GR is unaffected by the depletion of endogenous reducing thiols. The aforementioned inhibition of the MR may be prevented by in vivo co-treatment with glutathione monoethyl ester. Moreover, after acute depletion of glutathione, the reincubation in vitro of oxidized MR with reducing agents completely restores the steroid binding capacity, whereas only partial recovery can be obtained after chronic depletion. Interestingly, the concentration of receptor protein remains unchanged in the latter condition. These and other observations reported for other transcription factors lead us to speculate about the possible regulation of the steroid receptor bioavailability by an endogenous mechanism based on the regulation of the intracellular redox environment. Importantly, a low redox potential not only inhibits steroid binding, but also abrogates the nuclear trafficking of preformed steroid/receptor complexes. This feature is shared by both corticosteroid receptors, and may reflect an inhibitory mechanism related to that observed with protein phosphatase inhibitors rather than with the steroid-dependent activation of the receptor.

Inasmuch as the properties of the MR are almost unknown as compared to the overwhelming information about the GR, this review focuses on the former. Based on recent observations, an analysis of how apparently independent mechanisms may be involved in the regulation of the specific corticosteroid  receptor-dependent biological response.