Figure 3.

Hypothetical mechanisms underlying the effects of a FKBP51 antagonist administration on HPA axis activity. GR is normally localized in the cytosol in a complex with chaperone proteins including FKBP51. CORT increased during stress or at circadian peak induces the detachment of GR from FKBP51 and its binding to FKBP52, leading to GR nuclear translocation and binding to DNA. GR expressed in the anterior pituitary and PVN regulates CORT negative feedback by reducing POMC and CRH synthesis, respectively. Treatment with a FKBP51 will facilitate GR binding to FKBP52 thus GR genomic effect and negative feedback inhibition. This will ultimately result in decreased CORT secretion, and presumably in changes in ultradian rhythmicity.