The Role of FKBP51 in the regulation of the glucocorticoid receptor

Major depression is often correlated with a reduced glucocorticoid receptor (GR) sensitivity. Therefore, genes that reduce GR activity might play an important role in the understanding and the treatment of major depression. The immunophilin FKBP51 has been characterised as an important regulator of GR function. FKBP51 is a component of the hsp90-chaperone heterocomplex and increasing its levels inhibits GR transactivation in mammalian cells. The ability of FKBP51 to bind to hsp90 is necessary for its inhibitory function. Interestingly, FKBP51 shows reduced binding to the motor protein dynein, compared to its close homologue FKBP52. This is also reflected in the observation that nuclear transloction of GR after hormone binding is impaired in cells overexpressing FKBP51. To probe for an association between genes governing HPA activity and depression, we genotyped SNPs in 8 genes regulating GR, 5 of them chaperones. We found significant associations between response to antidepressants and recurrence of depressive episodes with SNPs in FKBP51 (Nat. Gen. 2004, 36: 1319–25). Moreover, these SNPs were also associated with changes in FKBP51 protein levels, which apparently triggered adaptive changes as we found also alterations in HPA axis hyperactivity. Interestingly, the SNPs also displayed increased response of FKBP51 mRNA levels to cortisol. Currently we are exploring the mechanistic basis for this SNP association.