The immunophilins, FK506 binding protein and cyclophilin, are discretely localized in the brain: relationship to calcineurin.
The immunosuppressant drugs cyclosporin A and FK506 bind to small, predominantly soluble proteins cyclophilin and FK506 binding protein, respectively, to mediate their pharmacological actions. The immunosuppressant actions of these drugs occur through binding of cyclophilin-cyclosporin A and FK506 binding protein-FK506 complexes to the calcium-calmodulin-dependent protein phosphatase, calcineurin, inhibiting phosphatase activity. Utilizing immunohistochemistry, in situ hybridization and autoradiography, we have localized protein and messenger RNA for FK506 binding protein, cyclophilin and calcineurin. All three proteins and/or messages exhibit a heterogenous distribution through the brain and spinal cord, with the majority of the localizations being neuronal. We observe a striking co-localization of FK506 binding protein and calcineurin in most brain regions and a close similarity between calcineurin and cyclophilin. FK506 binding protein and cyclophilin localizations largely correspond to those of calcineurin, although cyclophilin is enriched in some brain areas that lack calcineurin. The dramatic similarities in localization of FK506 binding proteins and cyclophilins with calcineurin suggest related functions.
Dawson
T M
TM
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Steiner
J P
JP
Lyons
W E
WE
Fotuhi
M
M
Blue
M
M
Snyder
S H
SH
D000591:Amino Acid Isomerases / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001483:Base Sequence; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D003524:Cyclosporins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense; D009928:Organ Specificity; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000033:anatomy & histology / Q000378:metabolism*; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D014316:Tritium
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D003524:Cyclosporins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014316:Tritium; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000591:Amino Acid Isomerases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus