Neural roles of immunophilins and their ligands

被引:93
作者
Sabatini, DM [1 ]
Lai, MM [1 ]
Snyder, SH [1 ]
机构
[1] JOHNS HOPKINS UNIV,SCH MED,DEPT NEUROSCI,BALTIMORE,MD 21205
关键词
calcineurin; cyclosporin A; dopamine; FK506; glutamate; inositol 1,4,5-trisphosphate; IP3; nerve growth factor; nitric oxide; N-methyl-D-aspartate (NMDA); rapamycin; ryanodine; serotonin;
D O I
10.1007/BF02740635
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:223 / 239
页数:17
相关论文
共 89 条
  • [71] IMMUNOPHILINS MEDIATE THE NEUROPROTECTIVE EFFECTS OF FK506 IN FOCAL CEREBRAL-ISCHEMIA
    SHARKEY, J
    BUTCHER, SP
    [J]. NATURE, 1994, 371 (6495) : 336 - 339
  • [72] THE EFFECT OF CYCLOSPORINE ON THE USE OF HOSPITAL RESOURCES FOR KIDNEY-TRANSPLANTATION
    SHOWSTACK, J
    KATZ, P
    AMEND, W
    BERNSTEIN, L
    LIPTON, H
    OLEARY, M
    BINDMAN, A
    SALVATIERRA, O
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1989, 321 (16) : 1086 - 1092
  • [73] A CYTOSOLIC BINDING-PROTEIN FOR THE IMMUNOSUPPRESSANT FK506 HAS PEPTIDYL-PROLYL ISOMERASE ACTIVITY BUT IS DISTINCT FROM CYCLOPHILIN
    SIEKIERKA, JJ
    HUNG, SHY
    POE, M
    LIN, CS
    SIGAL, NH
    [J]. NATURE, 1989, 341 (6244) : 755 - 757
  • [74] IMMUNOPHILINS AND THE NERVOUS-SYSTEM
    SNYDER, SH
    SABATINI, DM
    [J]. NATURE MEDICINE, 1995, 1 (01) : 32 - 37
  • [75] Peptidyl-prolyl cis-trans isomerases, cyclophilin, FK506-binding protein, and ninaA: four of a kind
    Stamnes, M. A.
    Zuker, C. S.
    [J]. CURRENT OPINION IN CELL BIOLOGY, 1990, 2 (06) : 1104 - 1107
  • [76] LIVER-TRANSPLANTATION .1.
    STARZL, TE
    DEMETRIS, AJ
    VANTHIEL, D
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1989, 321 (15) : 1014 - 1022
  • [77] LIVER-TRANSPLANTATION .2.
    STARZL, TE
    DEMETRIS, AJ
    VANTHIEL, D
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1989, 321 (16) : 1092 - 1099
  • [78] Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models
    Steiner, JP
    Hamilton, GS
    Ross, DT
    Valentine, HL
    Guo, HZ
    Connolly, MA
    Liang, S
    Ramsey, C
    Li, JHJ
    Huang, W
    Howorth, P
    Soni, R
    Fuller, M
    Sauer, H
    Nowotnik, AC
    Suzdak, PD
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (05) : 2019 - 2024
  • [79] HIGH BRAIN DENSITIES OF THE IMMUNOPHILIN FKBP COLOCALIZED WITH CALCINEURIN
    STEINER, JP
    DAWSON, TM
    FOTUHI, M
    GLATT, CE
    SNOWMAN, AM
    COHEN, N
    SNYDER, SH
    [J]. NATURE, 1992, 358 (6387) : 584 - 587
  • [80] Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A
    Steiner, JP
    Connolly, MA
    Valentine, HI
    Hamilton, GS
    Dawson, TM
    Hester, L
    Snyder, SH
    [J]. NATURE MEDICINE, 1997, 3 (04) : 421 - 428