Functional impact of FKBP51 on cellular pathways

Genome-wide association studies linked FKBP51 (FK506-binding protein, 51 kDa) to psychiatric diseases like major depression and post traumatic stress disorder. FKBP51 is a member of the immunophilin family and belongs to the group of hsp90 interacting TPR (tetratricopetide repeat) proteins. Genetic associations in addition suggest a connection of FKBP51 with the actions of antidepressants. To further explore the underlying mechanisms of FKBP51’s influence on the actions of antidepressants, we follow both hypothesis-driven and screening approaches to identify novel molecular networks in which FKBP51 operates. For example, we study the role of FKBP51 on the phosphatase calcineurin (CaN). CaN dephosphorylates members of NFAT transcription factors, which are also affected by antidepressants. Moreover we investigate the influence of FKBP51 on the protein kinase Akt (also protein kinase B). Akt is a key regulator of the PI3K/Akt pathway and is thought to be involved in the mode of action of several antidepressants. In order to proteins interacting with FKBP51, co-immunoprecipitation experiments with a series of FLAG-tagged FKBP51 mutants and HA-tagged Akt and CaN are carried out in HEK 293 cells. Moreover we elucidated the impact of FKBP51 overexpression on the transcriptional potence of NFAT-dependent promoters. The results obtained so far point to a potential common pathway in the actions of antidepressants and FKBP51.