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. 2002 Jan 15;361(Pt 2):401–407. doi: 10.1042/0264-6021:3610401

Modulation of type-1 Ins(1,4,5)P3 receptor channels by the FK506-binding protein, FKBP12.

Sheila L Dargan 1, Edward J A Lea 1, Alan P Dawson 1
PMCID: PMC1222321  PMID: 11772413

Abstract

FK506-binding protein (FKBP12) is highly expressed in neuronal tissue, where it is proposed to localize calcineurin to intracellular calcium-release channels, ryanodine receptors and Ins(1,4,5)P(3) receptors (InsP(3)Rs). The effects of FKBP12 on ryanodine receptors have been well characterized but the nature and function of binding of FKBP12 to InsP(3)R is more controversial, with evidence for and against a tight interaction between these two proteins. To investigate this, we incorporated purified type-1 InsP(3)R from rat cerebellum into planar lipid bilayers to monitor the effects of exogenous recombinant FKBP12 on single-channel activity, using K(+) as the current carrier. Here we report for the first time that FKBP12 causes a substantial change in single-channel properties of the type-1 InsP(3)R, specifically to increase the amount of time the channel spends in a fully open state. In the presence of ATP, FKBP12 can also induce co-ordinated gating with neighbouring receptors. The effects of FKBP12 were reversed by FK506. We also present data showing that rapamycin, at sub-optimal concentrations of Ins(2,4,5)P(3), decreases the rate of calcium release from cerebellar microsomes. These results provide evidence for a direct functional interaction between FKBP12 and the type-1 InsP(3)R.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bandyopadhyay A., Shin D. W., Ahn J. O., Kim D. H. Calcineurin regulates ryanodine receptor/Ca(2+)-release channels in rat heart. Biochem J. 2000 Nov 15;352(Pt 1):61–70. [PMC free article] [PubMed] [Google Scholar]
  2. Berridge M. J., Bootman M. D., Lipp P. Calcium--a life and death signal. Nature. 1998 Oct 15;395(6703):645–648. doi: 10.1038/27094. [DOI] [PubMed] [Google Scholar]
  3. Berridge M. J. Elementary and global aspects of calcium signalling. J Physiol. 1997 Mar 1;499(Pt 2):291–306. doi: 10.1113/jphysiol.1997.sp021927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bers D. M., Fill M. Coordinated feet and the dance of ryanodine receptors. Science. 1998 Aug 7;281(5378):790–791. doi: 10.1126/science.281.5378.790. [DOI] [PubMed] [Google Scholar]
  5. Bezprozvanny I., Ehrlich B. E. ATP modulates the function of inositol 1,4,5-trisphosphate-gated channels at two sites. Neuron. 1993 Jun;10(6):1175–1184. doi: 10.1016/0896-6273(93)90065-y. [DOI] [PubMed] [Google Scholar]
  6. Brillantes A. B., Ondrias K., Scott A., Kobrinsky E., Ondriasová E., Moschella M. C., Jayaraman T., Landers M., Ehrlich B. E., Marks A. R. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell. 1994 May 20;77(4):513–523. doi: 10.1016/0092-8674(94)90214-3. [DOI] [PubMed] [Google Scholar]
  7. Brown E. J., Albers M. W., Shin T. B., Ichikawa K., Keith C. T., Lane W. S., Schreiber S. L. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 1994 Jun 30;369(6483):756–758. doi: 10.1038/369756a0. [DOI] [PubMed] [Google Scholar]
  8. Bultynck G., De Smet P., Rossi D., Callewaert G., Missiaen L., Sorrentino V., De Smedt H., Parys J. B. Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)-binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor. Biochem J. 2001 Mar 1;354(Pt 2):413–422. doi: 10.1042/0264-6021:3540413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bultynck G., De Smet P., Weidema A. F., Ver Heyen M., Maes K., Callewaert G., Missiaen L., Parys J. B., De Smedt H. Effects of the immunosuppressant FK506 on intracellular Ca2+ release and Ca2+ accumulation mechanisms. J Physiol. 2000 Jun 15;525(Pt 3):681–693. doi: 10.1111/j.1469-7793.2000.t01-1-00681.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cameron A. M., Nucifora F. C., Jr, Fung E. T., Livingston D. J., Aldape R. A., Ross C. A., Snyder S. H. FKBP12 binds the inositol 1,4,5-trisphosphate receptor at leucine-proline (1400-1401) and anchors calcineurin to this FK506-like domain. J Biol Chem. 1997 Oct 31;272(44):27582–27588. doi: 10.1074/jbc.272.44.27582. [DOI] [PubMed] [Google Scholar]
  11. Cameron A. M., Steiner J. P., Roskams A. J., Ali S. M., Ronnett G. V., Snyder S. H. Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux. Cell. 1995 Nov 3;83(3):463–472. doi: 10.1016/0092-8674(95)90124-8. [DOI] [PubMed] [Google Scholar]
  12. Cameron A. M., Steiner J. P., Sabatini D. M., Kaplin A. I., Walensky L. D., Snyder S. H. Immunophilin FK506 binding protein associated with inositol 1,4,5-trisphosphate receptor modulates calcium flux. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1784–1788. doi: 10.1073/pnas.92.5.1784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Clardy J. The chemistry of signal transduction. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):56–61. doi: 10.1073/pnas.92.1.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ferris C. D., Huganir R. L., Snyder S. H. Calcium flux mediated by purified inositol 1,4,5-trisphosphate receptor in reconstituted lipid vesicles is allosterically regulated by adenine nucleotides. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2147–2151. doi: 10.1073/pnas.87.6.2147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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. 1989 Oct 26;341(6244):758–760. doi: 10.1038/341758a0. [DOI] [PubMed] [Google Scholar]
  16. Jayaraman T., Brillantes A. M., Timerman A. P., Fleischer S., Erdjument-Bromage H., Tempst P., Marks A. R. FK506 binding protein associated with the calcium release channel (ryanodine receptor). J Biol Chem. 1992 May 15;267(14):9474–9477. [PubMed] [Google Scholar]
  17. Jeyakumar L. H., Ballester L., Cheng D. S., McIntyre J. O., Chang P., Olivey H. E., Rollins-Smith L., Barnett J. V., Murray K., Xin H. B. FKBP binding characteristics of cardiac microsomes from diverse vertebrates. Biochem Biophys Res Commun. 2001 Mar 9;281(4):979–986. doi: 10.1006/bbrc.2001.4444. [DOI] [PubMed] [Google Scholar]
  18. Kanoh S., Kondo M., Tamaoki J., Shirakawa H., Aoshiba K., Miyazaki S., Kobayashi H., Nagata N., Nagai A. Effect of FK506 on ATP-induced intracellular calcium oscillations in cow tracheal epithelium. Am J Physiol. 1999 Jun;276(6 Pt 1):L891–L899. doi: 10.1152/ajplung.1999.276.6.L891. [DOI] [PubMed] [Google Scholar]
  19. Lam E., Martin M. M., Timerman A. P., Sabers C., Fleischer S., Lukas T., Abraham R. T., O'Keefe S. J., O'Neill E. A., Wiederrecht G. J. A novel FK506 binding protein can mediate the immunosuppressive effects of FK506 and is associated with the cardiac ryanodine receptor. J Biol Chem. 1995 Nov 3;270(44):26511–26522. doi: 10.1074/jbc.270.44.26511. [DOI] [PubMed] [Google Scholar]
  20. Liu J., Albers M. W., Wandless T. J., Luan S., Alberg D. G., Belshaw P. J., Cohen P., MacKintosh C., Klee C. B., Schreiber S. L. Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry. 1992 Apr 28;31(16):3896–3901. doi: 10.1021/bi00131a002. [DOI] [PubMed] [Google Scholar]
  21. Marx S. O., Ondrias K., Marks A. R. Coupled gating between individual skeletal muscle Ca2+ release channels (ryanodine receptors) Science. 1998 Aug 7;281(5378):818–821. doi: 10.1126/science.281.5378.818. [DOI] [PubMed] [Google Scholar]
  22. Marx S. O., Reiken S., Hisamatsu Y., Jayaraman T., Burkhoff D., Rosemblit N., Marks A. R. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000 May 12;101(4):365–376. doi: 10.1016/s0092-8674(00)80847-8. [DOI] [PubMed] [Google Scholar]
  23. Mezna M., Michelangeli F. Effects of thimerosal on the transient kinetics of inositol 1,4,5-trisphosphate-induced Ca2+ release from cerebellar microsomes. Biochem J. 1997 Jul 1;325(Pt 1):177–182. doi: 10.1042/bj3250177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Michikawa T., Hirota J., Kawano S., Hiraoka M., Yamada M., Furuichi T., Mikoshiba K. Calmodulin mediates calcium-dependent inactivation of the cerebellar type 1 inositol 1,4,5-trisphosphate receptor. Neuron. 1999 Aug;23(4):799–808. doi: 10.1016/s0896-6273(01)80037-4. [DOI] [PubMed] [Google Scholar]
  25. Peterson R. T., Beal P. A., Comb M. J., Schreiber S. L. FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem. 2000 Mar 10;275(10):7416–7423. doi: 10.1074/jbc.275.10.7416. [DOI] [PubMed] [Google Scholar]
  26. Poirier S. N., Poitras M., Chorvatova A., Payet M. D., Guillemette G. FK506 blocks intracellular Ca2+ oscillations in bovine adrenal glomerulosa cells. Biochemistry. 2001 May 29;40(21):6486–6492. doi: 10.1021/bi010207k. [DOI] [PubMed] [Google Scholar]
  27. Schreiber S. L. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991 Jan 18;251(4991):283–287. doi: 10.1126/science.1702904. [DOI] [PubMed] [Google Scholar]
  28. Siekierka J. J., Hung S. H., Poe M., Lin C. S., Sigal N. H. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature. 1989 Oct 26;341(6244):755–757. doi: 10.1038/341755a0. [DOI] [PubMed] [Google Scholar]
  29. Supattapone S., Worley P. F., Baraban J. M., Snyder S. H. Solubilization, purification, and characterization of an inositol trisphosphate receptor. J Biol Chem. 1988 Jan 25;263(3):1530–1534. [PubMed] [Google Scholar]
  30. Thrower E. C., Mobasheri H., Dargan S., Marius P., Lea E. J., Dawson A. P. Interaction of luminal calcium and cytosolic ATP in the control of type 1 inositol (1,4,5)-trisphosphate receptor channels. J Biol Chem. 2000 Nov 17;275(46):36049–36055. doi: 10.1074/jbc.M000970200. [DOI] [PubMed] [Google Scholar]

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