Molecular and Chemical Neuropathology

, Volume 17, Issue 1, pp 65–77 | Cite as

Postreceptor modulation of cAMP accumulation in rat brain particulate fraction after ischemia— Involvement of protein kinase C

  • Krystyna Domańska-Janik
  • Sonia Pylova
Original Articles

Abstract

The brain cyclic AMP generation was studied in rats subjected to 15 min of cardiac arrest. We have used a particulate, synaptoneurosomal fraction to demonstrate the effect of ischemia in vivo on the responsiveness of adenylate cyclase (AC) system. It has been shown that, although there is a slight decrease in AC activity after ischemia, the in vitro fractions produce more cAMP in response to a variety of stimuli, suggesting an indirect, nonadenylate cyclase activation mechanism.

For elucidation of this mechanism we have probed phorbol-12,13-dibutyrate (PDBu) as a direct PKC activator, forskolin to activate the catalytic subunit of AC, and cholera toxin (CT) for stabilizing the active, GTP-bound form of stimulatory guanine nucleotide binding protein (Gs). All these postreceptor AC modulators as well as the receptor activators such as adenosine and α1-adrenergic agonists markedly enhanced cAMP production in the rat brain particulate fraction, although the postischemic hyperactive response to these stimuli was still present. However, when AC was stimulated by the combination of CT and PDBu, cAMP responses were identical in both control and postischemic fractions.

The data, taken together, support the hypothesis that ischemia increases cAMP accumulation by facilitating the postreceptor AC activation through a PKC-involving pathway and by promoting the stronger coupling of membrane AC receptors with G-protein.

Protein kinase C (PKC) activity during cerebral ischemia was also investigated. In contradistinction to our expectation PKC decreased significantly in the ischemic brain to 85% of the control activity in the cytosol and 72% in the membranes. However, in the incubated postischemic brain particulate fraction a relative increase in the membranebound form of the enzyme, from 30% for control to 53% for ischemia, was observed. This may suggest that ischemia-induced membrane changes could promote the enzyme translocation/activation during recovery, resulting in the sensitization of cAMP producing system.

Index Entries

Protein kinase C cerebral ischemia cAMP accumulation postreceptor modulation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bailey N. T. J. (1975)Statistical Methods in Biology, pp. 15–18, Engl. University Press, London.Google Scholar
  2. Banschbach M. W. and Geison R. L. (1974) Post-mortem increase in rat cerebral hemisphere diglyceride pool size.J. Neurochem. 23, 875–877.PubMedCrossRefGoogle Scholar
  3. Blomqvist Ph., Lindvall O., Stenevi U., and Wieloch T. (1985) Cyclic AMP concentrations in rat neocortex and hippocampus during and following incomplete ischemia: Effects of central noradrenergic neurons, prostaglandins and adenosine.J. Neurochem. 44, 1345–1353.PubMedCrossRefGoogle Scholar
  4. Crumrine R. C., Dubyak G., and La Manna J. C. (1990) Decreased protein kinase C activity during cerebral ischemia and after reperfusion in the adult rat.J. Neurochem. 55, 2001–2007.PubMedCrossRefGoogle Scholar
  5. Domańska-Janik K., Łazarewicz J., Noremberg K., Strosznajder J., and Zalewska T. (1985) Metabolic disturbances of synaptosomes isolated from ischemic gerbil brain.Neurochem. Res. 10, 573–589.Google Scholar
  6. Domańska-Janik K. and Pylova S. (1989) Rapid enhancement of cAMP accumulation in rat brain particulate fraction after ischemia.J. Tissue Reaction 11, 73–79.Google Scholar
  7. Domańska-Janik K. and Zalewska T. (1988) Calcium activated protein kinase (PKC) and calcium activated neutral protease (CANPs) in gerbil ischemic brain.Neurochem. Int. 13 (Suppl. 1), 106.Google Scholar
  8. Domańska-Janik K. and Zalewska T. (1992). Effect of brain ischemia on protein kinase C.J. Neurochem. 58, 1432–1439.PubMedCrossRefGoogle Scholar
  9. Donaldson J., Kendall D. A., and Hill S. J. (1990) Discriminatory effects of for-skolin and EGTA on the indirect cyclic AMP responses to histamine, noradrenaline, 5-hydroxytryptamine and glutamate in guinea-pig cerebral cortical slices.J. Neurochem. 54, 1484–1491.PubMedCrossRefGoogle Scholar
  10. Duman R. S., Karbon E. W., Harrington C., and Enna S. J. (1986) An examination of the involvement of phospholipases A2 and C in the α-adrenergic and ψ-aminobutyric acid receptor modulation of cyclic AMP accumulation in rat brain slices.J. Neurochem. 47, 800–810.PubMedCrossRefGoogle Scholar
  11. Fredholm B. B., Lindgren E., Lindstrom K., and Nordstedt C. (1987) α-Adrenoreceptor stimulation, but not muscarinic stimulation, increases cyclic AMP accumulation in brain slices due to protein kinase-C mediated enhancement of adenosine receptor effects.Acta Physiol. Scand. 131, 543–551.PubMedCrossRefGoogle Scholar
  12. Globus M. Y., Ginsberg M. D., Dietrich W. D., Busto R., and Scheinberg P. (1987) Substantia nigra lesion protects against ischemic damage in the striatum.Neurosci. Lett. 80, 251–256.PubMedCrossRefGoogle Scholar
  13. Globus M. Y.-T., Busto R., Dietrich W. D., Martinez E., Valdes I., and Ginsberg M. D. (1989) Direct evidence for acute and massive norepinephrine release in the hippocampus during transient ischemia.J. Cereb. Blood Flow Metab. 9, 892–896.PubMedGoogle Scholar
  14. Gross R. A. and Ferrendelli J. A. (1980) Mechanisms of cyclic AMP regulation in cerebral anoxia and their relationship to glycogenolysis.J. Neurochem. 34, 1309–1318.PubMedCrossRefGoogle Scholar
  15. Harisk S. J., Raul B., and Martinez E. (1982) Norepinephrine regulation of cerebral glycogen utilization during seizures and ischemia.J. Neurol. Sci. 2, 409–414.Google Scholar
  16. Hollingsworth E. B., McNeal E. T., Burton J. L., Williams R. J., Daly J. W., and Creveling C. R. (1985) Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: Cyclic adenosine 3′∶5′-monophosphate generating systems, receptors and enzymes.J. Neurosci. 5, 2240–2253.PubMedGoogle Scholar
  17. Inoue M., McHugh M., and Pappius M. (1991) The effect of α-adrenergic receptor blockers prazosin and yohimbine on cerebral metabolism and biogenic amine content of traumatized brain.J. Cereb. Blood Flow Metab. 11, 242–252.PubMedGoogle Scholar
  18. Johnson R. D. and Minneman K. P. (1986) Characterization of α1-adrenoreceptors which increase cyclic AMP accumulation in rat cerebral cortex.Eur. J. Pharmacol. 129, 293–305.PubMedCrossRefGoogle Scholar
  19. Kababian J. W., Petsold G. L., and Greengard P. (1972) Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain and in similarity to the dopamine-receptor.Proc. Nat. Acad. Sci. USA 69, 2145–2149.CrossRefGoogle Scholar
  20. Kabayashi M., Lust W. D., and Passonneau J. V. (1977) Concentrations of energy metabolites and cyclic nucleotides during and after bilateral ischemia in the gerbil cerebral cortex.J. Neurochem. 29, 53–59.CrossRefGoogle Scholar
  21. Karbon E. W., Shenolikar S., and Enna S. J. (1986) Phorbol esters enhance neurotransmitter-stimulated cyclic AMP production in rat brain slices.J. Neurochem. 47, 1566–1575.PubMedCrossRefGoogle Scholar
  22. Karpachev V. G., Jakhina S. A., Mansumbayeva R.M., Tazibayeva D. C., Konovalov A. A., Ytescheva S. M., Bakapaieva Ch. K., Kadbyallev A. K., Kiselova H. G., and Mambetoaieva B. C. (1986) Experimental therapy of disturbances of higher nervous activity during the postresuscitation period, inAbstracts of International Symposium “Results and prospects of the development of modern reanimatology”, Moscow, p. 72.Google Scholar
  23. Lowry O. H., Rosebrough N. J., Farr A. L., and Randall R. L. (1951) Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193, 265–275.PubMedGoogle Scholar
  24. Manev H., Costa E., Wroblewski J. T., and Guidotti A. (1990) Abusive stimulation of excitatory amino acid receptors: A strategy to limit neurotoxicity.FASEB J. 4, 2789–2797.PubMedGoogle Scholar
  25. McPhail L. C., Clayton C. C., and Snyderman R. (1984) A potential second messenger role for unsaturated fatty acids: Activation of Ca2+-dependent protein kinase.Science 224, 622–625.PubMedCrossRefGoogle Scholar
  26. Nishizuka Y. (1986) Studies and perspectives of protein kinase C.Science 233, 305–312.PubMedCrossRefGoogle Scholar
  27. Nordstedt C. and Fredholm B. B. (1987) Phorbol-12,13-Dibutyrate enhances the cyclic AMP accumulation in rat hippocampal slices induced by adenosine analogues.Naunyn-Schmiedeberg’s Arch. Pharmacol. 355, 136–142.Google Scholar
  28. Sugden D. and Klein D. C. (1988) Activators of protein kinase C act at a postreceptor site to amplify cyclic AMP production in rat pinealocytes.J. Neurochem. 50, 149–155.PubMedCrossRefGoogle Scholar
  29. Zivin J. A., Kochhar A., and Saitoh T. (1990) Protein phosphorylation during ischemia.Stroke 21 (Suppl. III), 117–121.Google Scholar

Copyright information

© Humana Press 1992

Authors and Affiliations

  • Krystyna Domańska-Janik
    • 1
  • Sonia Pylova
    • 2
  1. 1.Department of NeurochemistryMedical Research Centre. Polish Academy of SciencesWarsawPoland
  2. 2.Laboratory of Experimental Physiology and Resuscitation of the OrganismAcademy of Medical Sciences of the USSRUSSR

Personalised recommendations