IMMUNOSUPPRESSANT FK506 PROMOTES NEURITE OUTGROWTH IN CULTURES OF PC12 CELLS AND SENSORY GANGLIA

The immunosuppressant drug FK506 acts by binding to receptor proteins, FK506-binding proteins (FKBPs), which in turn can bind to and regulat e a Ca2+-dependent phosphatase, calcineurin, and a Ca2+ release channe l, the ryanodine receptor. Based on our findings in regeneration model s that levels of FKBPs during neural regeneration parallel those of gr owth-associated protein GAP43, a calcineurin substrate that regulates neurite extension, we examined effects of FK506 in PC12 rat pheochromo cytoma cells and in rat sensory ganglia. FK506 enhances neurite outgro wth in both systems by increasing sensitivity to nerve growth factor. Blockade of FK506 actions in sensory ganglia by rapamycin, an FK506 an tagonist, establishes that these effects involve FKBPs. Rapamycin itse lf stimulates neurite outgrowth in PC12 cells. These drug effects are detected at subnanomolar concentrations, suggesting therapeutic applic ation in diseases involving neural degeneration.