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 regulate a Ca(2+)-dependent phosphatase, calcineurin, and a Ca2+ release channel, the ryanodine receptor. Based on our findings in regeneration models that levels of FKBPs during neural regeneration parallel those of growth-associated protein GAP43, a calcineurin substrate that regulates neurite extension, we examined effects of FK506 in PC12 rat pheochromocytoma cells and in rat sensory ganglia. FK506 enhances neurite outgrowth in both systems by increasing sensitivity to nerve growth factor. Blockade of FK506 actions in sensory ganglia by rapamycin, an FK506 antagonist, establishes that these effects involve FKBPs. Rapamycin itself stimulates neurite outgrowth in PC12 cells. These drug effects are detected at subnanomolar concentrations, suggesting therapeutic application in diseases involving neural degeneration.
Lyons
W E
WE
Division of Toxicological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
George
E B
EB
Dawson
T M
TM
Steiner
J P
JP
Snyder
S H
SH
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D017950:Ganglia, Sensory / Q000166:cytology* / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D009414:Nerve Growth Factors / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects*; D016716:PC12 Cells; D011090:Polyenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D009414:Nerve Growth Factors; D011090:Polyenes; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus