NEURAL ROLES OF IMMUNOPHILINS AND THEIR LIGANDS

The immunophilins are a family of proteins that are receptors for immu nosuppressant drugs, such as cyclosporin A, FK506,and rapamycin. They occur in two classes, the FK506-binding proteins (FKBPs), which bind F K506 and rapamycin, and the cyclophilins, which bind cyclosporin A. Im munosuppressant actions of cyclosporin A and FK506 derive from the dru g-immunophilin complex binding to and inhibiting the phosphatase calci neurin. Rapamycin binds to FKBP and the complex binds to Rapamycin And FKBP-12 Target (RAFT). RAFT affects protein translation by phosphoryl ating p70-S6 kinase, which phosphorylates the ribosomal S6 protein, an d 4E-BP1, a repressor of protein translation initiation. Immunophilin levels are much higher in the brain than in immune tissues, and levels of FKBP12 increase in regenerating neurons in parallel with GAP-43. I mmunophilin ligands, including nonimmunosuppressants that do not inhib it calcineurin, stimulate regrowth of damaged peripheral and central n eurons, including dopamine, serotonin, and cholinergic neurons in inta ct animals. FKPB12 is physiologically associated with the ryanodine an d inositol 1,4,5-trisphosphate (IP3) receptors and regulates their cal cium flux. By influencing phosphorylation of neuronal nitric oxide syn thase, FKBP12 regulates nitric oxide formation, which is reduced by FK 506.