Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

Although the immediate receptors (immunophilins) of the immunosuppressants cyclosporin A (CsA) and FK506 are distinct, their similar mechanisms of inhibition of cell signaling suggest that their associated immunophilin complexes interact with a common target. We report here that the complexes cyclophilin-CsA and FKBP-FK506 (but not Cyclophilin, FKBP, FKBP-rapamycin, or FKBP-506BD) competitively bind to and inhibit the CA(2+)- and calmodulin-dependent phosphatase Calcineurin, although the binding and inhibition of Calcineurin do not require Calmodulin. These results suggest that Calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that Cyclophilin and FKBP mediate the actions of CsA and FK506, respectively, by forming drug-dependent complexes with and altering the activity of calcineurin-calmodulin.