Role of chaperones in signal transduction of the glucocorticoid receptor

The glucocorticoid receptor (GR) has been reported in neuroendocrine studies to have reduced sensitivity in patients suffering from major depression. GR is transformed to a DNA binding transcriptional activator upon binding of hormone. To become competent of hormone binding, the receptor goes through a cascade of chaperone-assisted folding steps. Heat shock protein 90 (hsp90) appears to be the central platform in this process. Recent genetic studies revealed that one of the chaperone molecules is involved with the treatment response of a subgroup of depressive patients. We embarked in elucidating the role of chaperones in signal transduction of glucocorticoids with the aim to explore potential ways of modulating this pathway via intervention at chaperones. More specifically, we focussed on the function of hsp90, BAG-1, and the large immunophilins FKBP51 and FKBP52 with respect to GR signaling by pharmacological intervention and mutational analysis.