Functional impact of FKBP5 on the phosphatase calcineurin

Genome-wide association studies confirm FKBP51 as an important factor in stress-related diseases like depression. FKBP51 is a member of the immunophilin family and is incorporated into heterocomplexes with Hsp90 and its client proteins like steroid receptors or kinases. The large FKBPs are characterized by a PPIase, which is drug-inhibitable by binding either immunosuppressive agent FK506 or rapamycin. It is now firmly established that FKBP51 is a potent initiator of the glucocorticoid receptor. This function may explain why FKBP51 determines the efficiency of antidepressant treatment. To shed more light on potential actions of FKBP51 that could explain how it accelerates improvement by antidepressants, this project explores a potential influence of FKBP51 on the phosphatase calcineurin (CaN). CaN dephosphorylates members of NFAT transcription factors, which have been implicated in the actions of antidepressants. For investigation of more direct physical interaction, co-immunoprecipitation experiments with a series of FLAG-tagged FKBP51 mutants, transfected into COS-7 cells were established. Initial results confirmed binding of FKBP51 to CaN also in the absence of FK506. To test the functional consequence of the interaction between FKBP51 and CaN, a reporter gene assay was performed, which showed a inhibiting effect of FKBP51 on NFAT-dependent promoters. These results point to a potential common pathway in the actions of antidepressants and FKBP51.