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Immunophilins and nervous system

Nature Medicine volume 1, pages 32–37 (1995)Cite this article

Abstract

The search for immunosuppressant drugs to increase the success of organ transplantation led to the discovery of the immunophilins, proteins that interface with a range of signal transduction systems inside cells, especially in the nervous and immune systems. Here we review how these interesting molecules work and consider their therapeutic potential.

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References

  1. F.S., Palmer, R.M.J. & Higgs, E.A. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol. Rev. 43, 109–142 (1991).

    PubMed  Google Scholar 

  2. Dawson, T.M. & Snyder, S.H. Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J. Neurvsci. 14, 5147–5159 (1994).

    Article  CAS  Google Scholar 

  3. Handschumacher, R.E., Harding, M.W., Rice, J., Drugge, R.J. & Speicer, D.W. Cyclophilin: A specific cytosolic binding protein for cyclosporin A. Science 226, 544–547 (1984).

    Article  CAS  PubMed  Google Scholar 

  4. Fischer, G., Bang, H. & Mech, C. Determination I of enzymatic catalysis for the cis-fraws-isomerization of peptide binding in projine-containing peptides. Biomed. Biochim. Acta. 43, 1101–1111 (1984).

    CAS  PubMed  Google Scholar 

  5. Fischer, G., Wittmann-Liebold, B., Lang, K., Kiefhaber, T. & Schmid, F.X. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 340, 351–352 (1989).

    Google Scholar 

  6. Steinmann, B., Bruckner, P. & Superti-Furga, P. Cyclosporin A slows collagen triple-helix formation in vivo: indirect evidence for a physiological role of peptidyl-prolyl cis-trans-isomerase. J. biol. Chem. 266, 1299–1303 (1991).

    CAS  PubMed  Google Scholar 

  7. Lodish, H.F. & Kong, N. Cyclosporin A inhibits an i litial step in folding of transferrrin within the endoplasmic reticulum. J. biol. Chem. 266, 14835–14838 (1991).

    CAS  PubMed  Google Scholar 

  8. Ochiai, T., K., Nakajima & Nagat, M. Effect of a new immunosuppressive agent, FK 506, on heterotopic cardiac allotransplantation I in the rat. Transplant Proc. 19, 1284–1286 (1987).

    CAS  PubMed  Google Scholar 

  9. Siekierka, J.J., Hung, S.H.Y., Poe, M., Lin, C.S. & Sigal, N.H. A cytosolic binding protein for the immunosuppressant FK506 has peptk y1-proly1 isomerase activity but is distinct from cyclophilin. Nature 341, 755–757 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Harding, M.W., Galat, A., Uehling, D.E. & Schreiber, S.L. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341, 758–760 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Bierer, B.E. et al. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunmophilin and either FK506 and rapamycin. Proc. natn. Acad. Sci. U.S.A. 87, 9231–9235 (1990).

    Article  CAS  Google Scholar 

  12. Schreiber, S.L. Chemistry and biology of the immunophilms and their immunosuppressive ligands. Science 253, 283–287 (1991).

    Article  Google Scholar 

  13. Dumont, et al. et al. The immunosuppressive and toxic effects of FK-506 are mechanistically related: Pharmacology of a novel antagonist of FK-506 and rapamycin. J. exp. Med. 176, 751–760 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Bierer, B.E. et al. Probining immunosuppressant action with a non-natural im-munophilin ligand. Science 250, 556–559 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Arber, S., Krause, K.H. & Caroni, P. S-cyclosporin is retained intracellularly via a unique COOH-terminal sequence and co-localizes with the calcium storage protein calreticulin. J. cell Biol. 116, 113–125 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Bram, R.J., Hung, D.T., Martin, P.K., Schreiber, S.L. & Crabtree, R. Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location. Mol. cell Biol. 13, 4760–4769 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bergsma, D.J. et al The cyclophilin multigene family of peptidyl-prolyl isomerases. Characterization of three separate human isoforms. J. biol Chem. 266, 23204–23214 (1991).

    CAS  PubMed  Google Scholar 

  18. Kieffer, L.J. et al. Cyclophilin-40, a protein with homology to the P59 component of the steroid receptor complex. Cloning of the cDNA and further characterization. J. biol. Chem. 268, 12303–12310 (1993).

    CAS  PubMed  Google Scholar 

  19. Jin, Y.-J. et al. Molecular cloning of a membrane-associated human FK506-and rapamycin-binding protein, FKBP-13. Proc. natn. Acad. Sci. U.S.A. 88, 6677–6681 (1991).

    Article  CAS  Google Scholar 

  20. Tottrup, A., Glavind, E.B. & Suane, D. Involvement of the L-arginine-nitric oxide pathway in internal anal sphincter relaxation. Gastoenterology 102, 409–415 (1992).

    Article  CAS  Google Scholar 

  21. Jin, Y-J. & S.J., Burakoff The 25-kDa FK506-binding protein is localized in the nucleus and associates with casein Kinase II and nucleolin. Proc. natn. Acad. Sci. USA 90, 7769–7773 (1993).

    Article  CAS  Google Scholar 

  22. Lebeau, M.C. et al. P59, an hsp 90-binding protein. Cloning and sequencing of its cDNA and preparation of a peptide-directed polyclonal antibody. J. biol. Chem. 267, 4281–4284 (1992).

    CAS  PubMed  Google Scholar 

  23. Liu, J. et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66, 807–815 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Friedman, J. & Weissman, I. Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Cell 66, 799–806 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Liu, J. et al. Inhibition of T cell signalling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry 31, 3896–3901 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Nelson, P.A. et al. Immunosuppressive activity of [MeBm2t.1-, D-diaminobu-tyryl-8-, and D-diaminopropyl-8-cyclosporin analogues correlates with inhibition of calcineurin phosphatase activity. J. Immunol. 150, 2139–2147 (1993).

    CAS  PubMed  Google Scholar 

  27. Clipston, N.A. & Crabtree, G.R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695–697 (1992).

    Article  Google Scholar 

  28. O'Keefe, S.J., J., Tamura, R. L. Kincaid, M.J., Tocci & E.A., O'Neill FK-506-and 64. CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 357, 692–694 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Flanagan, W.M., B., Corthesy, R.J., Bram & G.R., Crabtree Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352, 754–755 (1991).

    Article  Google Scholar 

  30. Kuo, C.J. et al. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358, 70–73 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Chung, J.C., J., Kuo, G.R., Crabtree & J., Blenis Rapamycin-FKBP specifically blocks growth-dependent activation of and signalling by the 70 kd S6 protein kinases. Cell 69, 1227–1236 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Price, D.J., J.R., Grove, V., Calvo, J., Auruch & B.E., Bierer Rapamycin-induced inhi-69. billon of the 70-kilodalton S6 protein kinase. Science 257, 973–977 (1992).

    Article  CAS  PubMed  Google Scholar 

  33. Albers, M.W. et al. An FKBP-rapamycin-sensitive, cyclin-dependent kinase activity that correlates with the FKBP-rapamycin-induced Gl arrest point in MG-63 cells. Ann. N. Y. Acad. Sci. 696, 54–62 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Jayaraman, T. & A.R., Marks Rapamycin-FKBP12 blocks proliferation, induces differentiation, and inhibits cdc2 kinase activity in a myogenic cell line. J. biol. Chem. 268, 25385–25388 (1993).

    CAS  PubMed  Google Scholar 

  35. Morice, W.G., G., Wiederrecht, G.J., Brunn, J.J., Siekierka & R.T., Abraham Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes. J. biol. Chem. 268, 22737–22745 (1993).

    CAS  PubMed  Google Scholar 

  36. Kunz, J. et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for Gl progression. Cell 73, 585–596 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Heitman, J., N.R., Movva & M.N., Hall Targets for cell cycle arrest by the immuno-suppressant rapamycin in yeast. Science 253, 905–909 (1994).

    Article  Google Scholar 

  38. Sabatini, D.M., H., Erdjument-Bromage, M., Lui, P., Tempst & S.H., Snyder RAFT1 (Rapamycin and FKBP12 Target): a mammalian protein that binds to FKBP12 in rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Brown, E.J. et al. A mammalian protein targeted by Gl-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Chen, Y. et al. A putative sirolimus (rapamycin) effector protein. Biochem. biophys. Res. Commun. 203, 1–7 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Cantley, L.C. et al. Oncogenes and signal transduction. Cell 64, 281–302 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Fleischer, S. & M., Inui Biochemistry and biophysics of excitation-contraction coupling. Ann. Rev. Biophys. Biophys. Chem. 18, 333–364 (1989).

    Article  CAS  Google Scholar 

  43. Sorrentino, V. & P., Volpe . TIPS 14, 98–102 (1993).

    CAS  PubMed  Google Scholar 

  44. Marks, A.R. et al. Molecular cloning and characterization of the ryanodine receptor/junctional channel complex cDNA from skeletal muscle sarcoplasmic reticulum. Proc. natn. Acad. Sci. USA 86, 8683–8687 (1989).

    Article  CAS  Google Scholar 

  45. Takeshima, H. et al. Primary structure and expression from complementary DNA of skeletal muscle ryanodine receptor. Nature 339, 439–445 (1989).

    Article  CAS  PubMed  Google Scholar 

  46. Otsu, K. et al. Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum. J. biol. Chem. 265, 13472–13483 (1990).

    CAS  PubMed  Google Scholar 

  47. Collins, J.H. Sequence analysis of the ryanodine receptor: Possible association with a 12K, FK506-binding immunophilin/protein kinase C inhibitor. Biochem. biophys. Res. Commun. 178, 1288–1290 (1991).

    Article  CAS  PubMed  Google Scholar 

  48. Jayraman, T. et al. FK506 binding protein associated with the calcium release channel (Ryanodine receptor). J. biol. Chem. 267, 9474–9477 (1992).

    Google Scholar 

  49. Brillantes, A.B. et al. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell 77, 513–523 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Ferris, C.D. & S.H., Snyder Inositol 1,4,5-trisphosphate activated calcium channels. Ann. Rev. Physiol. 54, 469–488 (1991).

    Article  Google Scholar 

  51. Berridge, M.J. & R.F., Irvine Inositol phosphates and cell signalling. Nature 341, 197–204 (1989).

    Article  CAS  PubMed  Google Scholar 

  52. Gardner, P. Patch clamp studies of lymphocyte activation. Ann. Rev. Immun. 8, 231–252 (1990).

    Article  CAS  Google Scholar 

  53. Khan, A.A., J.P., Steiner, M.G., Klein, M.F., Schneider & S.H., Snyder IP3 receptor: localization to plasma membrane of T cells and cocapping with the T cell receptor. Science 257, 815–818 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. Furuichi, T. et al. Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400. Nature 342, 32–38 (1989).

    Article  CAS  PubMed  Google Scholar 

  55. Cameron, A.M. et al. Immunophilin FKBP associated with inositol 1,4,5-trisphosphate receptor modulates calcium flux. Proc. natn. Acad. Sci. USA .(in the press)

  56. Helekar, S.A., D., Char, S., Neff & J., Patrick Prolyl isomerase requirement for the expression of functional homo-oligomeric ligand-gated ion channels. Neuron 12, 179–189 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Bram, R.J. & G.R., Crabtree Calcium signalling in T cells stimulated by a cyclophilin B-binding protein. Nature 371, 355–358 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, T., P.K., Donahoe & A.S., Zervos Specific interaction of type I receptors of the TGF-p family with the immunophilin FFKBP-12. Science 265, 674–676 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Maki, N., F., Sekiguchi, J., Nishimaki, K., Miwa, T., Hayano, N., Takahashi & M., Suzuki Complementary DNA encoding the human T-cell FK506-binding protein, a peptidylprolyl cis-trans isomerase distinct from cyclophilin. Proc. natn. Acad. Sci. USA 87, 5440–5443 (1990).

    Article  CAS  Google Scholar 

  60. Steiner, J.P. et al. High brain densities of the immunophilin FKBP colocalized with calcineurin. Nature 358, 584–587 (1992).

    Article  CAS  PubMed  Google Scholar 

  61. Kuno, T. et al. Distinct cellular expression of calcineurin Aa and Ab in rat brain. J. Neurochem. 58, 1643–1651 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Jones, D.T. & Reed, R.R. Molecular cloning of five GTP-binding protein cDNA species from rat olfactory neuroepithelium. J. biol. Chem. 262, 14241–14249 (1987).

    CAS  PubMed  Google Scholar 

  63. Dawson, T.M. et al. Immunosuppressant, FK506, enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc. natn. Acad. Sci. USA 90, 9808–9812 (1993).

    Article  CAS  Google Scholar 

  64. Bredt, D.S. & S.H., Snyder Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc. natn. Acad. Sci. USA 86, 9030–9033 (1989).

    Article  CAS  Google Scholar 

  65. Garthwaite, J., G., Garthwaite, R.M.J., Palmer & S., Moncada NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur. J. Pharmac. 172, 413–416 (1989).

    Article  CAS  Google Scholar 

  66. Bredt, D.S. & S.H., Synder Isolation of nitric oxide synthetase, a calmodulin-re-quiring enzyme. Proc. natn. Acad. Sci. USA 87, 682–685 (1990).

    Article  CAS  Google Scholar 

  67. Choi, D.W. Bench to bedside: the glutamate connection. Science 258, 241–243 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Bredt, D.S., C.D., Ferris & S.H., Snyder Nitric oxide synthase regulatory sites. J. biol. Chem. 267, 10976–10981 (1992).

    CAS  PubMed  Google Scholar 

  69. Dinerman, J.L. & S.H., Snyder Multiple phosphorylations of neuronal nitric oxide synthase inhibit catalytic activity. Neuropharm. (1994).(in the press)

  70. Sharkey, J. & S.P., Butcher Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 371, 336–339 (1994).

    Article  CAS  PubMed  Google Scholar 

  71. Meiri, K.F., L.E., Bickerstaff & J.E., Schwob Monoclonal antibodies show that kinase C phosphorylation of GAP-43 during axonogenesis is both spatially and temporally restricted in vivo. J. cell Biol. 112, 991–1005 (1991).

    Article  CAS  PubMed  Google Scholar 

  72. Lyons, W.E., E.B., George, T.M., Dawson, J.P., Steiner & S.H., Snyder Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC-12 cells and sensory ganglia. Proc. natn. Acad. Sci. USA 91, 3191–3195 (1994).

    Article  CAS  Google Scholar 

  73. Gold, B.G., T., Storm-Dickerson & D.R., Austin The immunosuppressant FK506 increases functional recovery and nerve regeneration following peripheral nerve injury. Restorative Neurol. Neurosci. 6, 287–296 (1994).

    CAS  Google Scholar 

  74. Lyons, W.E., J.P., Steiner, S.H., Snyder & T.M., Dawson Neuronal regeneration enhances the expression of the immunophilin FKBP. J. Neurosci. (1994).(in the press)

  75. Hultsch, T., M.W., Albers, S.L., Schreiber & R.J., Hohman Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription. Proc. natn. Acad. Sci. USA 88, 6229–6233 (1991).

    Article  CAS  Google Scholar 

  76. Steiner, J.P., T.M., Dawson & S.H., Snyder Immunophilin regulation of neuro-transmitter release. Soc. Neurosci. Abst. (1993). (Abstract)

  77. Hirsch, D.B., J.P., Steiner, T.M., Dawson, A., Mammen, E., Hayek & S.H., Snyder Neurotransmitter release regulated by nitric oxide in PC-12 cells and brain synap-tosomes. Cur. Biol. 3, 749–754 (1993).

    Article  CAS  Google Scholar 

  78. Hanbauer, L., D., Wink, Y., Osawa, G.M., Edelman & J., Gaily Role of nitric oxide in NMDA-evoked release of [3H]dopamine from striatal slices. NeuroReport 3, 409–412 (1992).

    Article  CAS  PubMed  Google Scholar 

  79. Luban, J. et al. Cell 73, 1067–1078 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Francke, E.K. et al. Nature 372, 359–360 (1994).

    Article  Google Scholar 

  81. Thali, M. et al. Nature 372, 363–364 (1994).

    Article  CAS  PubMed  Google Scholar 

  82. Stancato, L.F. et al. J. biol. Chem. 269, 22157–22161 (1994).

    CAS  PubMed  Google Scholar 

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  1. Departments of Neuroscience, Pharmacology & Molecular Sciences, Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, USA

    Solomon H. Snyder & David M. Sabatini

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Snyder, S., Sabatini, D. Immunophilins and nervous system. Nat Med 1, 32–37 (1995). https://doi.org/10.1038/nm0195-32

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