Skip to main content
SpringerLink
Log in

The Lipid Peroxidation Product 4-Hydroxynonenal Potently and Selectively Inhibits Synaptic Plasma Membrane Ecto-ATPase Activity, A Putative Regulator of Synaptic ATP and Adenosine

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Synaptic plasma membrane (SPM)-bound, extracellular-facing (ecto) ATPases are Mg2+- or Ca2+-activated enzymes that regulate the synaptic levels of the excitatory neurotransmitter ATP and provide ADP for the further ecto-nucleotidase-mediated production of the inhibitory neuromodulator adenosine. The present results show that low concentrations (IC50 = 4 μM) of the lipid peroxidation product 4-hydroxynonenal (HNE) inhibited up to about 80% of the ecto-ATPase activity of SPM purified from rat brain cerebral cortex. In contrast, low concentrations of HNE did not inhibit the activity of the “intracellular”-facing Na+, K+, Mg2+-ATPase. In addition, the inhibition of SPM ecto-ATPase activity by HNE was largely irreversible and pH-dependent. Furthermore, structure-activity studies demonstrate that inhibition was dependent on the presence of the reactive functional groups of HNE. These findings suggest that HNE selectively inhibits SPM ecto-ATPase activity by a mechanism that may involve the covalent modification of functionally-critical nucleophilic amino acids. It is proposed that inhibition of SPM ecto-ATPase activity could contribute to the mechanisms by which lipid peroxidation and HNE formation promote excitotoxicity.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Inoue, K., Koizumi, S., and Ueno, S. 1996. Implications of ATP receptors in brain functions. Prog. Neurobiol., 50:483–492.

    Google Scholar 

  2. North, R. A., and Barnard, E. A. 1997. Nucleotide receptors. Curr. Opin. Neurobiol., 7:346–357.

    Google Scholar 

  3. Ralevic, V., and Burnstock, G. 1998. Receptors for purines and pyrimidines. Pharmacol. Rev., 50:413–492.

    Google Scholar 

  4. Zimmermann, H. 1996. Biochemistry, Localization and functional roles of ecto-nucleotidases in the central nervous system. Prog. Neurobiol., 49:589–618.

    Google Scholar 

  5. Zimmermann, H., Braun, N., Kegel, B., and Heine, P. 1998. New insights into molecular structure and function of ecto-nucleotidases in the nervous system. Neurochem. Int., 32:421–425.

    Google Scholar 

  6. Richardson, P. J., and Brown, S. J. 1987. ATP release from affinity-purified rat cholinergic nerve terminals. J. Neurochem., 48:622–630.

    Google Scholar 

  7. James, S., and Richardson, P. J. 1993. Production of adenosine from extracellular ATP at the striatal cholinergic synapse. J. Neurochem., 60:219–227.

    Google Scholar 

  8. Dunwiddie, T. V., Diao, L., and Proctor, W. R. 1997. Adenine nucleotides undergo rapid, quantitative conversion to adenosine in the extracellular space in rat hippocampus. J. Neurosci., 17:7673–7682.

    Google Scholar 

  9. Cunha, R. A., Sebastiao, A. M., and Ribeiro, J. A. 1998. Inhibition by ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases into adenosine and channeling to adenosine A1 receptors.

  10. Esterbauer, H., Schaur, R. J., and Zollner, H. 1991. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Rad. Biol. Med., 11:81–128.

    Google Scholar 

  11. Uchida, K., and Stadtman, E. R. 1992. Modification of histidine residues in proteins by reaction with 4-hydroxynonenal. Proc. Natl. Acad. Sci. USA, 89:4544–4548.

    Google Scholar 

  12. Uchida, K., and Stadtman, E. R. 1992. Selective cleavage of thioether linkage in proteins modified with 4-hydroxynonenal. Proc. Natl. Acad. Sci. USA, 89:5611–5615.

    Google Scholar 

  13. Szweda, L. I., Uchida, K., Tsai, L., and Stadtman, E. R. 1993. Inactivation of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. Selective modification of an active-site lysine. J. Biol. Chem., 268:3342–3347.

    Google Scholar 

  14. Kruman, I., Bruce-Keller, A. J., Bredesen, D., Waeg, G., and Mattson, M. P. 1997. Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci., 17:5089–5100.

    Google Scholar 

  15. Mark, R. J., Lovell, M. A., Markesbery, W. R., Uchida, K., and Mattson, M. P. 1997. A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid β-peptide. J. Neurochem., 68:255–264.

    Google Scholar 

  16. Mattson, M. P. 1998. Modification of ion homeostasis by lipid peroxidation: Roles in neuronal degeneration and adaptive plasticity. Trends Neurosci., 20:53–57.

    Google Scholar 

  17. Vietta, M., Frassetto, S. S., Battastini, A. M. O., Bello-Klein, A., Moreira, C., Dias, R. D., and Sarkas, J. J. F. 1996. Sensitivity of ATPase-ADPase activities from synaptic plasma membranes of rat forebrain to lipid peroxidation in vitro and the protective effect of vitamin E. Neurochem. Res., 21:299–304.

    Google Scholar 

  18. Benzi, G., Arnaboldi, G. R., Ghigini, B., and Villa, R. F. 1994. Synaptosomal Non-mitochondrial ATPase activities: Age-related alterations by chronic normobaric intermittent hypoxia. Neurochem. Int., 25:61–67.

    Google Scholar 

  19. Nagy, A. K., Walton, N. Y., and Treiman, D. M. 1997. Reduced cortical ecto-ATPase activity in rat brain during prolonged status epilepticus induced by sequential administration of lithium and pilocarpine. Mol. Chem. Neuropathol., 31:135–147.

    Google Scholar 

  20. Nagy, A. K., Shuster, T. A., and Delgado-Escueta, A. V. 1986. Ecto-ATPase of mammalian synaptosomes. Identification and enzymic characterization. J. Neurochem., 47:976–986.

    Google Scholar 

  21. Hohmann, J., Kowalewski, H., Vogel, M., and Zimmermann, H. 1993. Isolation of a Ca2+ or Mg2+-activated ATPase (ecto-ATPase) from bovine brain synaptic membranes. Biochem. Biophys. Acta, 1152:146–154.

    Google Scholar 

  22. Foley, T. D. 1997. 5-HPETE is a potent inhibitor of Neuronal Na+, K+-ATPase activity. Biochem. Biophys. Res. Commun., 235:374–376.

    Google Scholar 

  23. Booth, R. F. G., and Clark, J. B. 1978. A rapid method for the preparation of relatively pure metabolically competent synaptosomes from rat brain. Biochem. J., 176:363–370.

    Google Scholar 

  24. Kanner, B. I. 1978. Active transport of γ-aminobutyric acid by membrane vesicles isolated from rat brain. Biochemistry, 17:1207–1211.

    Google Scholar 

  25. Rhoads, D. E., Petersen, N. A., Sankaran, H., and Raghupathy, E. 1982. Inhibitory effect of scorpion venom on the uptake of amino acids by synaptosomes and synaptosomal membrane vesicles. Biochem. Pharmacol., 31:1875–1879.

    Google Scholar 

  26. Jones, D. H., and Matus, A. I. 1974. Isolation of synaptic plasma membrane from brain by combined flotation-sedimentation density gradient centrifugation. Biochim. Biophys. Acta, 356:276–287.

    Google Scholar 

  27. Doughty, M. J. 1978. Ciliary Ca2+-ATPase from the excitable membrane of Paramecium. Some properties and purification by affinity chromatography. Comp. Biochem. Physiol., 37:911–917.

    Google Scholar 

  28. Siems, W. G., Hapner, S. J., and Kuijk, F. J. G. M. 1996. 4-Hydroxynonenal Inhibits Na+, K+-ATPase. Free Rad. Biol., Med. 20:215–223.

    Google Scholar 

  29. Inoue, K., Koizumi, S., Nakazawa, K. 1995. Glutamate-evoked release of adenosine 5′-triphosphate causing an increase in intracellular calcium in hippocampal neurones. Neuroreport, 6:437–440.

    Google Scholar 

  30. Inoue, K., Nakazawa, K., Fugimori, W., and Takanaka, A. 1992. Extracellular adenosine 5′-triphosphate-evoked glutamate release in cultured rat hippocampal neurons. Neurosci. Lett., 134:215–218.

    Google Scholar 

  31. Jianguo, G. G., and MacDermott, A. B. 1997. Activation of ATP P2x receptors elicits glutamate release from sensory neuron synapses. Nature, 389:749–753.

    Google Scholar 

  32. Khakh, B. S., and Henderson, G. 1998. ATP receptor-mediated enhancement of fast excitatory neurotransmitter release in the brain. Mol. Pharmacol., 54:372–378.

    Google Scholar 

  33. Koles, L., Wirkner, K., Thummler, S., Furst, S., and Illes, P. 1998. Interaction between N-methyl-D-aspartate (NMDA)-and P2 receptors in rat prefrontal cortical slices. Naunyn-Schmiedeberg's Arch. Pharmacol., 358(suppl. 3):R781

    Google Scholar 

  34. Daval, J.-L., Nehlig, A., and Nicolas, F. 1991. Physiological and Pharmacological properties of adenosine: Therapeutic implications. Life Sci., 49:1435–1453.

    Google Scholar 

  35. Craig, C., and White, T. D. 1993. N-Methyl-D-aspartate-and non-N-methyl-D-aspartate-evoked adenosine release from rat cortical slices: Distinct purinergic sources and mechanisms of release. J. Neurochem., 60:1073–1080.

    Google Scholar 

  36. Noremberg, W., Wirkner, K., and Illes, P. 1997. Effect of adenosine and some of its structural analogs on the conductance of NMDA receptor channels in a subset of rat neostriatal neurones. Brit. J. Pharmacol., 122:71–80.

    Google Scholar 

  37. Koles, L., Wirkner, K., Richter, M., Abmann, H., Norenberg, W., and Illes, P. 1998. Adenosine receptor-mediated inhibition of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-isozazole-4-propionic acid (AMPA) receptor channels in rat neostriatum. Naunyn-Schmiedeberg's Arch. Pharmacol., 358(suppl. 1):R126.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section on Neurochemistry, LCS, DICBR, National Institute on Alcohol Abuse and Alcoholism, NIH, 12420 Parklawn Drive, Room 158, Rockville, MD, 20852. Phone:

    Timothy D. Foley

  2. Section on Biochemistry, Department of Chemistry, University of Scranton, Loyola Hall, Scranton, PA, 18510

    Timothy D. Foley

Authors
  1. Timothy D. Foley
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Foley, T.D. The Lipid Peroxidation Product 4-Hydroxynonenal Potently and Selectively Inhibits Synaptic Plasma Membrane Ecto-ATPase Activity, A Putative Regulator of Synaptic ATP and Adenosine. Neurochem Res 24, 1241–1248 (1999). https://doi.org/10.1023/A:1020921006221

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020921006221

Search

Navigation