Neural roles of immunophilins and their ligands.
The immunophilins are a family of proteins that are receptors for immunosuppressant drugs, such as cyclosporin A, FK506, and rapamycin. They occur in two classes, the FK506-binding proteins (FKBPs), which bind FK506 and rapamycin, and the cyclophilins, which bind cyclosporin A. Immunosuppressant actions of cyclosporin A and FK506 derive from the drug-immunophilin complex binding to and inhibiting the phosphatase calcineurin. Rapamycin binds to FKBP and the complex binds to Rapamycin And FKBP-12 Target (RAFT). RAFT affects protein translation by phosphorylating p70-S6 kinase, which phosphorylates the ribosomal S6 protein, and 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. Immunophilin ligands, including nonimmunosuppressants that do not inhibit calcineurin, stimulate regrowth of damaged peripheral and central neurons, including dopamine, serotonin, and cholinergic neurons in intact animals. FKPB12 is physiologically associated with the ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors and regulates their calcium flux. By influencing phosphorylation of neuronal nitric oxide synthase, FKBP12 regulates nitric oxide formation, which is reduced by FK506.
Sabatini
D M
DM
Johns Hopkins University School of Medicine, Department of Neuroscience, Baltimore, MD 21205, USA.
Lai
M M
MM
Snyder
S H
SH
D000818:Animals; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000502:physiology*; D002645:Chickens; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D018448:Models, Immunological; D009416:Nerve Regeneration / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019696:Peptidylprolyl Isomerase / Q000187:drug effects / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011090:Polyenes; D016194:Receptors, N-Methyl-D-Aspartate; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus; D016559:Tacrolimus