High brain densities of the immunophilin FKBP colocalized with calcineurin.
The immunophilins cyclophilin and FK506 binding protein (FKBP) are small, predominantly soluble proteins that bind the immunosuppressant drugs cyclosporin A and FK506, respectively, with high affinity, and which seem to mediate their pharmacological actions. The Ca(2+)-dependent protein phosphatase, calcineurin, binds the cyclophilin-cyclosporin A and FKBP-FK506 complexes, indicating that calcineurin might mediate the actions of these drugs. A physiological role for the immunophilins in the nervous system is implied by a close homology between the structure of NINA A, a protein in the neural retina of Drosophila, and cyclophilin, as well as by the high density of FKBP messenger RNA in brain tissue. Here we report that the levels of FKBP and mRNA in rat brain are extraordinarily high and that their regional localization is virtually identical to that of calcineurin, indicating that there may be a physiological link between calcineurin and the immunophilins. We also show that at low concentrations FK506 and cyclosporin A enhance the phosphorylation of endogenous protein substrates in brain tissue and in intact PC12 cells, indicating that these drugs may inhibit phosphatase activity by interacting with the immunophilin-calcineurin complexes.
Steiner
J P
JP
Department of Neuroscience, Johns Hopkins University School of Medicine.
Dawson
T M
TM
Fotuhi
M
M
Glatt
C E
CE
Snowman
A M
AM
Cohen
N
N
Snyder
S H
SH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D019703:Calcineurin; D002118:Calcium / Q000494:pharmacology; D002148:Calmodulin-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism*; D008970:Molecular Weight; D009928:Organ Specificity; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D013462:Sulfur Radioisotopes; D016559:Tacrolimus / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014316:Tritium
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D013462:Sulfur Radioisotopes; D014316:Tritium; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D022021:Tacrolimus Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D016559:Tacrolimus