Skip to main content
Log in

Isoform-Specific Membrane Translocation of Protein Kinase C After Ischemic Preconditioning

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Mild cerebral anoxic/ischemic/stress insults promote ‘tolerance’ and thereby protect the brain from subsequent ‘lethal’ anoxic/ischemic insults. We examined whether specific activation of PKC α, δ, ∈, or ζ isoforms is associated with ischemic preconditioning (IPC) in rat brain. IPC was produced by a 2-minute global cerebral ischemia. Membrane and cytosolic fractions of the hippocampi were immunoblotted using specific antibodies for PKCα, δ, ∈, and ζ. PKCα showed a significant translocation to the membrane fraction from 30 min to 4 h and PKCδ at 4 h following IPC. In contrast, the membrane/cytosol ratio of PKC∈ showed a tendency to decrease at 30 min and 8 h, and the membrane/cytosol ratio of PKCζ was significantly decreased from 30 min to 24 h following IPC. These findings indicate PKC isoform-specific membrane translocations in the hippocampus after brief global brain ischemia and suggest that activation of PKCα and PKCδ may be associated with IPC-induced tolerance in the rat hippocampus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. Kato, H., Araki, T., Murase, K., and Kogure, K. 1992. Induction of tolerance to ischemia: Alterations in second-messenger systems in the gerbil hippocampus. Brain Res. Bull. 29:559–565.

    Google Scholar 

  2. Li, Y. W., Whittaker, P., and Kloner, R. A. 1992. The transient nature of the effect of ischemic preconditioning on myocardial infarct size and ventricular arrhythmia. Am. Heart J. 123:346–353.

    Google Scholar 

  3. Kobayashi, S., Harris, V. A., and Welsh, F. A. 1995. Spreading depression induces tolerance of cortical neurons to ischemia in rat brain. J. Cereb. Blood Flow Metab. 15:721–727.

    Google Scholar 

  4. Murry, C. E., Jennings, R. B., and Reimer, K. A. 1986. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136.

    Google Scholar 

  5. Matsushima, K. and Hakim, A. M. 1995. Transient forebrain ischemia protects against subsequent focal cerebral ischemia without changing cerebral perfusion. Stroke 26:1047–1052.

    Google Scholar 

  6. Heurteaux, C., Lauritzen, I., Widmann, C., and Lazdunski, M. 1995. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning. Proc. Natl. Acad. Sci. USA 92:4666–4670.

    Google Scholar 

  7. Liu, G. S., Thornton, J., Van Winkle, D. M., Stanley, A. W., Olsson, R. A., and Downey, J. M. 1991. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 84:350–356.

    Google Scholar 

  8. Pérez-Pinzón, M. A., Mumford, P. L., Rosenthal, M., and Sick, T. J. 1996. Anoxic preconditioning in hippocampal slices: Role of adenosine. Neuroscience 75:687–694.

    Google Scholar 

  9. Node, K., Kitakaze, M., Sato, H., Minamino, T., Komamura, K., Shinozaki, Y., Mori, H., and Hori, M. 1997. Role of intracellular Ca2+ in activation of protein kinase C during ischemic preconditioning. Circulation 96:1257–1265.

    Google Scholar 

  10. Osten, P., Hrabetova, S., and Sacktor, T. C. 1996. Differential downregulation of protein kinase C isoforms in spreading depression. Neurosci. Lett. 221:37–40.

    Google Scholar 

  11. Bilinska, M., Maczewski, M., and Beresewicz, A. 1996. Donors of nitric oxide mimic effects of ischaemic preconditioning on reperfusion induced arrhythmias in isolated rat heart. Mol. Cell. Biochem. 160-161:265–271.

    Google Scholar 

  12. Gaggiano, A. O. and Kraig, R. P. 1998. Neuronal nitric oxide synthase expression is induced in neocortical astrocytes after spreading depression. J. Cereb. Blood Flow Metab. 18:75–87.

    Google Scholar 

  13. Centeno, J. M., Orti, M., Salom, J. B., Sick, T. J., and Pérez-Pinzón, M. A. 1999. Nitric oxide is involved in anoxic preconditioning neuroprotection in rat hippocampal slices. Brain Res. 836:62–69.

    Google Scholar 

  14. Gidday, J. M., Shah, A. R., Maceren, R. G., Wang, Q., Pelligrino, D. A., Holtzman, D. M., and Park, T. S. 1999. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J. Cereb. Blood Flow Metab. 19:331–340.

    Google Scholar 

  15. Ping, P., Zhang, J., Huang, S., Cao, X., Tang, X., Li, R., Zheng, Y., Qiu, Y., Clerk, A., Sugden, P., Han, J., and Bolli, R. 1999. PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits. Am. J. Physiol. 277:H1771–H1785.

    Google Scholar 

  16. Gonzalez-Zulueta, M., Feldman, A. B., Klesse, L. J., Kalb, R. G., Dillman, J. F., Parada, L. F., Dawson, T. M., and Dawson, V. L. 2000. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc. Natl. Acad. Sci. USA 97:436–441.

    Google Scholar 

  17. Koistinaho, J., Pasonen, S., Yrjanheikki, J., and Chan, P. H. 1999. Spreading depression-induced gene expression is regulated by plasma glucose. Stroke 30:114–119.

    Google Scholar 

  18. Koponen, S., Keinanen, R., Roivainen, R., Hirvonen, T., Narhi, M., Chan, P. H., and Koistinaho, J. 1999. Spreading depression induces expression of calcium-independent protein kinase C subspecies in ischaemia-sensitive cortical layers: Regulation by N-methyl-D-aspartate receptors and glucocorticoids. Neuroscience 93:985–993.

    Google Scholar 

  19. Kurkinen, K., Keinanen, R., Li, W., and Koistinaho, J. 2001. Preconditioning with spreading depression activates specifically protein kinase C delta. NeuroReport 12:269–273.

    Google Scholar 

  20. Koponen, S., Goldsteins, G., Keinanen, R., and Koistinaho, J. 2000. Induction of protein kinase C delta subspecies in neurons and microglia after transient global brain ischemia. J. Cereb. Blood Flow Metab. 20:93–102.

    Google Scholar 

  21. Inagaki, K., Kihara, Y., Hayashida, W., Izumi, T., Iwanaga, Y., Yoneda, T., Takeuchi, Y., Suyama, K., Muso, E., and Sasayama, S. 2000. Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of deltaisoform of protein kinase C in rat ventricular myocardium. Circulation 22:797–804.

    Google Scholar 

  22. Liu, G., Cohen, M., Mochly-Rosen, D., and Downey, J. 1999. Protein kinase C-epsilon is responsible for the protection of preconditioning in rabbit cardiomyocytes. J. Mol. Cell. Cardiol. 31:1937–1948.

    Google Scholar 

  23. Mizukami, Y., Kobayashi, S., Uberall, F., Hellbert, K., Kobayashi, N., and Yoshida, K. 2000. Nuclear Mitogen-activated Protein Kinase Activation by Protein Kinase C{zeta} During Reoxygenation after Ischemic Hypoxia. J. Biol. Chem. 275:19921–19927.

    Google Scholar 

  24. Wang, Y. and Ashraf, M. 1999. Role of protein kinase C in mitochondrial K +ATP channel-mediated protection against Ca2+ overload injury in rat myocardium. Circ. Res. 84:1156–1165.

    Google Scholar 

  25. Yoshida, K., Kawamura, S., Mizukami, Y., and Kitakaze, M. 1997. Implication of protein kinase C-Alpha, Delta, and Epsilon isoforms in ischemic preconditioning in perfused rat hearts. J. Biochem. (Tokyo) 122:506–511.

    Google Scholar 

  26. Zhao, J., Wightman, L., Sugden, P. H., Stewart, L., Miller, A. D., Latchman, D. S., and Marber, M. S. 1998. The expression of constitutively active isotypes of protein kinase C to investigate preconditioning. J. Biol. Chem. 273:23072–23079.

    Google Scholar 

  27. Pérez-Pinzón, M. A. 1999. Excitatory and inhibitory pathways for anoxic preconditioning neuroprotection in hippocampal slices. Adv. Exp. Med. Biol. 471:165–173.

    Google Scholar 

  28. Pérez-Pinzón, M. A., Born, J. G., and Centeno, J. M. 1999. Calcium and increased excitability promote tolerance against anoxia in hippocampal slices. Brain Res. 833:20–26.

    Google Scholar 

  29. Plumier, J. C., David, J. C., Robertson, H. A., and Currie, R. W. 1997. Cortical application of potassium chloride induces the low-molecular weight heat shock protein (Hsp27) in astrocytes. J. Cereb. Blood Flow Metab. 17:781–790.

    Google Scholar 

  30. Taga, K., Patel, P. M., Drummond, J. C., Cole, D. J., and Kelly, P. J. 1997. Transient neuronal depolarization induces tolerance to subsequent forebrain ischemia in rats. Anesthesiology 87:918–925.

    Google Scholar 

  31. Nishizaki, T. and Ikeuchi, Y. 1996. Adenosine evokes potassium currents by protein kinase C activated via a novel signalling pathway in superior colliculus neurons. FEBS Lett. 378:16470–16476.

    Google Scholar 

  32. Tanaka, C. and Nishizuka, Y. 1994. The protein kinase C family for neuronal signaling. Annu. Rev. Neurosci. 17:551–567.

    Google Scholar 

  33. Miettinen, S., Roivainen, R., Keinanen, R., Hokfelt, T., and Koistinaho, J. 1996. Specific induction of protein kinase C delta subspecies after transient middle cerebral artery occlusion in the rat brain: Inhibition by MK-801. J. Neurosci. 16:6236–6245.

    Google Scholar 

  34. Downey, J. M., Cohen, M. V., Ytrehus, K., and Liu Y. 1994. Cellular mechanisms in ischemic preconditioning: The role of adenosine and protein kinase C. Ann. NY Acad. Sci. 723:82–98.

    Google Scholar 

  35. Inagaki, K., Kihara, Y., Hayashida, W., Izumi, T., Iwanaga, Y., Yoneda, T., Takeuchi, Y., Suyama, K., Muso, E., and Sasayama, S. 2000. Anti-ischemic effect of a novel cardioprotective agent, JTV519, is mediated through specific activation of delta-isoform of protein kinase C in rat ventricular myocardium. Circulation 22:797–804.

    Google Scholar 

  36. Takeishi, Y., Jalili, T., Ball, N. A., and Walsh, R. A. 1999. Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. Circ. Res. 85:264–271.

    Google Scholar 

  37. Goldberg, M., Zhang, H. L., and Steinberg, S. F. 1997. Hypoxia alters the subcellular distribution of protein kinase C isoforms in neonatal rat ventricular myocytes. J. Clin. Invest. 99:55–61.

    Google Scholar 

  38. Gray, M. O., Karliner, J. S., and Mochly-Rosen, D. 1997. A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J. Biol. Chem. 272:30945–30951.

    Google Scholar 

  39. Shimizu, S., Nagayama, T., Jin, K. L., Zhu, L., Loeffert, J. E., Watkins, S. C., Graham, S. H., and Simon, R. P. 2001. bcl-2 Antisense treatment prevents induction of tolerance to focal ischemia in the rat brain. J. Cereb. Blood Flow Metab. 21:233–243.

    Google Scholar 

  40. Kawahara, N., Croll, S. D., Wiegand, S. J., and Klatzo, I. 1997. Cortical spreading depression induces long-term alterations of BDNF levels in cortex and hippocampus distinct from lesion effects: Implications for ischemic tolerance. Neurosci. Res. 29:37–47.

    Google Scholar 

  41. Jander, S., Schroeter, M., Peters, O., Witte, O. W., and Stoll, G. 2001. Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J. Cereb. Blood Flow Metab. 21:218–225.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurkinen, K., Busto, R., Goldsteins, G. et al. Isoform-Specific Membrane Translocation of Protein Kinase C After Ischemic Preconditioning. Neurochem Res 26, 1139–1144 (2001). https://doi.org/10.1023/A:1012322906824

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1012322906824

Navigation