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Regulation of N-Methyl-d-aspartate receptor-mediated calcium transport and norepinephrine release in rat hippocampus synaptosomes by polyamines

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Abstract

The role of polyamines (PA) synthesis in NMDA receptor-mediated45Ca2+ fluxes and norepinephrine release was studied in rat hippocampal synaptosomes. NMDA (50μM) caused a sharp (>2-fold) transient increase in PA synthesis regulating enzyme, ornithine decarboxylase (ODC) activity with concomitant elevation in PA levels in the order putrescine>spermidine>spermine. ODC inhibitor, α-difluoromethylornithine (DFMO), and NMDA antagonist, 2-amino-5-phosphonovaleric acid (D-AP5), both blocked increases in ODC activity and PA levels. Activation of NMDA receptors induced a sharp (3 to 4-fold) and quick (15 seconds) increase in45Ca2+ uptake by synaptosomes within 15 seconds of exposure at 37°C. The efflux of45Ca2+ and3H-norepinephrine (NE) release at 22°C from pre-loaded synaptosomes was also significantly (2 to 4-fold) enhanced by NMDA within 15 seconds. These NMDA receptor-mediated effects on calcium fluxes and NE release were blocked by NMDA receptor-antagonists (DAP-5 and MK-801) and PA synthesis inhibitor, DFMO and the DFMO inhibition nullified by exogenous putrescine. These observations establish that ODC/PA cascade play an important role in transduction of excitatory amino acid mediated signals at NMDA receptors.

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References

  1. Collingridge, G. L., and Lester, R. A. J. 1989. Excitatory amino acid receptors in the vertebrate central nervous system. Physiol. Rev. 40:143–210.

    Google Scholar 

  2. Mayer, M. L., Vycklicky, L., and Sernagor, E. 1989. A physiologist's view of the N-methyl-D-aspartate receptor: an allosteric ion channel with multiple regulatory sites. Drug Development Res. 17:263–280.

    Google Scholar 

  3. Monaghan, D. T., Bridges, R.J., and Cotman, C. W. 1989. The excitatory amino acid receptors: their classes, pharmacology and distinct properties in function of the central nervous system. Ann. Rev. Pharmacol. Toxicol. 29:365–402.

    Google Scholar 

  4. Ransom, R. W. and Stec, N. L. 1988. Comparative modulation of [3H]MK-801 binding to the N-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine, and polyamines. J. Neurochem. 51:830–836.

    PubMed  Google Scholar 

  5. Reynolds, I. J. and Miller, R. J. 1989. Ifenprodil is a novel type of N-methyl-D-asparate receptor antagonist interaction with polyamines. Mol. Pharmacol. 36:758–765.

    PubMed  Google Scholar 

  6. Sacaan, A. I. and Johnson, K. M. 1990. Characterization of the stimulatory and inhibitory effects of polyamines on [3H]TCP binding to the NMDA receptor iouophore complex. Mol. Pharmacol. 37:572–577.

    PubMed  Google Scholar 

  7. Williams, K., Romano, C., and Molinoff, P. B. V. 1989. Effects of polyamines on the binding of3H-MK-801 to the N-methyl-D-aspartate receptor. Pharmacological evidence for the existence of a polyamine recognition site. Mol. Pharmacol. 36:575–581.

    PubMed  Google Scholar 

  8. Collingridge, G. L. and Singer, W. 1990. Excitatory amino acid receptors and synaptic plasticity. Tr. Pharm. Sci. 11:290–296.

    Google Scholar 

  9. Lipton, S. A., and Kater, S. B. 1989. Neurotransmitter regulation of neuronal outgrowth, plasticity and survival. Tr. Neurosci. 12:265–270.

    Google Scholar 

  10. Dingledine, R., MacBain, C. J., and McNamara, J. O. 1990. Excitatory amino acid receptors in epilepsy. Tr. Pharm. Sci. 11:334–338.

    Google Scholar 

  11. Choi, D. W. 1988. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634.

    PubMed  Google Scholar 

  12. Durand, G. M., Bennett, M. V. and Zukin, R. S. 1993. Splice variants of the NMDA receptor NR1 identify domains involved in regulation by polyamines and protein kinase C. Proc. Natl. Acad. Scie. (US) 6731–6735.

  13. Mayer, M. L., and Miller, R. J. 1990. Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2+ in mammalian neurons. Tr. Pharm. Sci. 11:254–260.

    Google Scholar 

  14. Nicoletti, F., Wroblewski, J. T., Novelli, A., Acho, H., Guidotti, A., and Costa, E. 1986. The activation of inositol phospholipid metabolism as a signal transducing system for excitatory amino acids in primary cultures of cerebellar granule cells. J. Neurosci. 6:1905–1911.

    PubMed  Google Scholar 

  15. Sladeczek, F., Pin, J. P., Recasens, M., Bockaert, J., and Weiss, S. 1985. Glutamate stimulates inositol phosphate formation in striatal neurons. Nature 317:717–719.

    PubMed  Google Scholar 

  16. Vaccarino, F., Guidotti, A., and Costa, E. 1987. Ganglioside inhibition of glutamate-mediated protein kinase C translocation in primary cultures of cerebellar neurons. Proc. Natl. Acad. Sci. USA 84:8707–8711.

    PubMed  Google Scholar 

  17. Dumuis, A., Sebben, M., Haynes, L., Pin, J.-P., and Bockaert, J. 1988. NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 336:68–70.

    PubMed  Google Scholar 

  18. Lazarewicz, J. W., Wroblewski, J. R., and Costa, E. 1990. N-Methyl-D-asparate-sensitive glutamate receptors induce calciummediated arachidonic acid release in primary cultures of cerebellar granule cells. J. Neurochem. 55:1875–1881.

    PubMed  Google Scholar 

  19. Chetkovich, D. M., Gray, R., Johnston, D., and Sweatt, J. D. 1991. N-Methyl-D-aspartate receptor activation increases cAMP levels and voltage-gated Ca2+ channel activity in area CA1 of hippocampus. Proc. Natl. Acad. Sci. USA 88:6696–6700.

    PubMed  Google Scholar 

  20. Garthwaite, J., Charles, S. L., and Chess-Williams, R. 1988. Endothelium derived relaxing factor release on activation of NMDA receptors suggests its role as intracellular messenger in the brain. Nature 336:385–388.

    PubMed  Google Scholar 

  21. Novelli, A., Nicoletti, F., Wroblewski, J. T., Acho, H., Costa, E., and Guidotti, A. 1987. Excitatory amino acid receptors coupled with guanylate cyclase in primary cultures of cerebellar granule cells. J. Neurosci. 7:40–47.

    PubMed  Google Scholar 

  22. Klamm, E., Chen, S.-J., and Sweatt, J. D. 1991. Persistent protein kinase activation in the maintenance phase of long-term potentiation. J. Biol. Chem. 266:24253–24256.

    PubMed  Google Scholar 

  23. Bading, H., and Greenberg, M. E. 1991. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253:912–914.

    PubMed  Google Scholar 

  24. Szekeley, A. M., Barbaccia, M. L., Alho, H., and Costa, E. 1989. In primary cultures of cerebellar granule cells the activation of NMDA-sensitive glutamate receptors induces c-fos mRNA expression. Molec. Pharmacol. 35:401–408.

    Google Scholar 

  25. Fagg, G. E., and Matus, A. 1984. Selective association of N-methyl-aspartate and quisqualate types of L-glutamate receptor with brain postsynaptic membranes. Proc. Natl. Acad. Sci. USA 81:6876–6880.

    PubMed  Google Scholar 

  26. Greenamyre, J. T., and Young, A. B. 1989. Synaptic localization of striatal NMDA, quisqualate and kainate receptors. Neurosci. Lett. 101:133–137.

    PubMed  Google Scholar 

  27. Monaghan, D. T., and Cotman, C. W. 1986. Identification and properties of NMDA receptors in rat brain synaptic membranes. Proc. Natl. Acad. Sci. USA 83:7532–7536.

    PubMed  Google Scholar 

  28. Errington, M. L., Lynch, M. A., and Bliss, T. V. P. 1987. Longterm potentiation in the dentate gyrus: induction and increased glutamate release are blocked byd-amino-phosphonovalerate. Neuroscience 20:279–284.

    PubMed  Google Scholar 

  29. Koenig, H., Iqbal, Z., Goldstone, A., Siddiqui, F., and Lu, C. Y. 1989. NMDA receptor transduction: polymines as 2nd messengers mediating agonist-stimulated Ca2+ influx and transmitter release. J. Neurochem. 52(Suppl), S42.

    Google Scholar 

  30. Koening, H., Iqbal, Z., Goldstone, A., and Lu, C. 1991. Polyamines mediate presynaptic NMDA receptor responses in synaptosomes. J. Neurochem. 57(Suppl.), S15.

    PubMed  Google Scholar 

  31. Martin, D., Bustos, G. A., Bowe, M. A., Bray, S. D., and Nadler, J. V. 1991. Autoreceptor regulation of glutamate and aspartate release from slices of the hippocampal CA1 area. J. Neurochem. 56:1647–1655.

    PubMed  Google Scholar 

  32. Young, M. J., and Bradford, H. F. 1991. N-Methyl-D-aspartate releases excitatory amino acids in rat corpus striatum in vivo. J. Neurochem. 56:1677–1683.

    PubMed  Google Scholar 

  33. Nicholls, D. G. 1989. Release of glutamate, aspartate, and aminobutyric acid from isolated nerve terminals. J. Neurochem. 52:331–341.

    PubMed  Google Scholar 

  34. Clow, D. W., and Jhamandas, K. 1989. Characterization of L-glutamate action on the release of endogenous dopamine from the rat caudate-putamen. J. Pharmacol. Exp. Therap. 248:722–728.

    Google Scholar 

  35. Krebs, M. O., Desce, J. M., Kemel, M. L., Gauchy, C., Godeheu, G., Cheramy, A., and Glowinski, J. 1991. Glutamatergic control of dopamine release in the rat striatum:evidence for presynaptic N-methyl-D-aspartate receptors on dopaminergic nerve terminals. J. Neurochem. 56:81–85.

    PubMed  Google Scholar 

  36. Wang, J. K. T. 1991. Presynaptic glutamate receptors modulate dopamine release from striatal synaptosomes. J. Neurochem. 57:819–822.

    PubMed  Google Scholar 

  37. Fink, K., Bonisch, H., and Gothert, M. 1990. Presynaptic NMDA receptors stimulate noradrenaline release in the cerebral cortex. Eur. J. Pharmacol. 185:115–117.

    PubMed  Google Scholar 

  38. Pittaluga, A., and Raiteri, M. 1990. Release-enhancing glucinedependent presynaptic NMDA receptors exist on noradrenergic terminals of hippocampus. Eur. J. Pharmacol. 191:231–234.

    PubMed  Google Scholar 

  39. Iqbl Z. 1989. Role of calcium and polyamines in neuronal signal transduction. Plenary lecture at the 58th Annual Meeting of the Society of Biological Chemists (India).

  40. Wang, J. K. T., Andrews, H., and Thukral, V. 1992. Presynaptic glutamate receptors regulate noradrenaline release from isolated nerve terminals. J. Neurochem. 58:204–211.

    PubMed  Google Scholar 

  41. Augustine, G. J., Charlton, M. P., and Smith, S. J. 1987. Calcium action in synaptic transmitter release. Ann. Rev. Neurosci. 10:633–693.

    PubMed  Google Scholar 

  42. Retz, K. C., Young, A. C., and Coyle, J. T. 1982. Glutamate stimulation of45Ca2+ uptake by rat striatal synaptosomes. Eur. J. Pharmacol. 79:319–322.

    PubMed  Google Scholar 

  43. Simonato, M., Jope, R. S., Bianchi, C., and Beani, L. 1989. Lack of excitatory amino acid-induced effects on calcium fluxes measured with45Ca2+ in rat cerebral cortex synaptosomes. Neurochem. Res. 14:667–682.

    PubMed  Google Scholar 

  44. Adamson, P., Hajimohammadreza, I., Brammer, M. J., Campbell, I. C., and Meldrum, B. S. 1990. Presynaptic glutamate/quisqualate receptors: effects on synaptosomal free calcium concentrations. J. Neurochem. 55:1850–1854.

    PubMed  Google Scholar 

  45. Daniell, L. C. 1991. N-Methyl-D-aspartate increases cytoplasmic free calcium in mouse hippocampus. Neuropharmacology. 30:539–545.

    PubMed  Google Scholar 

  46. Tabor, C. W. and Tabor, H. 1984. Polyamines. Annu. Rev. Biochem. 53:749–790.

    PubMed  Google Scholar 

  47. Koenig, H., Goldstone, A. D., and Lu, C. Y. 1983. Polyamines regulate calcium fluxes in a rapid plasma membrane response. Nature 305:530–534.

    PubMed  Google Scholar 

  48. Koenig, H., Ean, C.-C., Goldstone, A. D., Lu, C. Y., and Trout, J. J. 1989. Polyamines mediate androgenic stimulation of calcium fluxes and membrane transport in rat heart myocytes. Circ. Res. 64:415–426.

    PubMed  Google Scholar 

  49. Koenig, H., Goldstone, A. D., Lu, C. Y., Iqbal, Z., Fan, C.-C., and Trout, J. J. 1989. Polyamines, hormone receptors and calcium fluxes,in The Physiology of Polymines (Bachrach U. and Heimer, Y. M., eds), CRC Press, vol. 1, pp. 57–81.

  50. Fan C.-C. and Koenig H. 1988. The role of polyamines in β-adrenergic stimulation of calcium influx and membrane transport in rat heart. J. Mol. Cell. Cardiol. 20:789–799.

    PubMed  Google Scholar 

  51. Koenig, H., Goldstone, A. D., and Lu, C. Y. 1983. β-Adrenergic stimulation of Ca2+fluxes, endocytosis, hexose tranpport and amino acid transport in mouse kidney cortex is mediated by polyamine synthesis. Proc. Natl. Acad. Sci. USA 80:7210–7214.

    PubMed  Google Scholar 

  52. Koenig, H., Goldstone, A. D., and Lu, C. Y. 1988. Polyamines are intracellular messengers in the β-adrenergic regulation of Ca2+ fluxes, [Ca2+]i and membrane transport in rat heart myocytes. Biochem. Biophys. Res. Commun. 153:1179–1185.

    PubMed  Google Scholar 

  53. Koenig, H., Goldstone, A. D., and Lu, C. Y. 1987. Neurotransmitters modulate Ca2+ influx and transport processes in brain capillaries: a new model for blood-brain barrier regulation (Abstr.), Ann. Neurol. 22:137–138.

    Google Scholar 

  54. Iqbal, Z., and Koenig, H. 1985. The role of polyamine synthesis in epilepsy induced by electroconvulsive shock and methionine sulfoximine. J. Neurochem. 44(Suppl.):S88.

    Google Scholar 

  55. Iqbal, Z., Koenig, H., Zimmerman, R., and Chisholm, R. 1991. ECS seizures, NMDA receptors and the ODC/polyamine cascade, Neurchem, Internat. 16:120.

    Google Scholar 

  56. Iqbal, Z., Siddiqui, F., Lu, C. and Koenig, H. 1993. Polyamines and NMDA receptors in electroconvulsive shock induced epileptic seizures. Soc. Neuroscie. Abstr. 19:1134.

    Google Scholar 

  57. Iqbal, Z., and Koenig, H. 1985. Polyamines appear to be second messengers in mediating calcium fluxes and neurotransmitter release in potassium depolarized synaptosomes. Biochem. Biophys. Res. Commun. 133:563–573.

    PubMed  Google Scholar 

  58. Djuhuus, R. 1981. Ornithine decarboxylase assay based on the retention of putrescine by a strong cation-exchange paper. Anal. Biochem. 113:352–353.

    PubMed  Google Scholar 

  59. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275.

    PubMed  Google Scholar 

  60. Watkins, J. C., and Olverman, H. J. 1987. Agonists and antagonists for excitatory amino acid receptors. Tr. Neurosci. 10:265–272.

    Google Scholar 

  61. Metcalf, B. W., Bey, P., Danzin, C., Jung, M. J., Casara, P., and Vevert, J. P. 1978. Catalytic irreversible inhibition of mammalian ornithine decarboxylase (EC 4.1.1.17) by substrate and product analogues. J. Am. Chem. Soc. 100:2552–2553.

    Google Scholar 

  62. Fage, D., Voltz, C., Scatton, B. and Carter, C. 1992. Selective release of spermine and spermidine from the rat striatum by NMDA receptor activators in vivo. J. Neurochem. 58:2170–2175.

    PubMed  Google Scholar 

  63. Iversen, L. L. 1994. MK-801 (Dizocilpine maleate)-NMDA receptor antagonist. Neurotransmissions. 10:1–4.

    Google Scholar 

  64. Wong, E. H. F., Kemp, J. A., Priestly, T., Knight, A. R., Woodruff, G. N., and Iversen, L. L. 1986. The antagonist MK-801 is a potent N-methyl-D-aspartate antagonist. Proc. Natl. Acad. Sci. USA 83:7104–7108.

    PubMed  Google Scholar 

  65. McNamara, J. O., Russell, R. D., Rigsbee, L., and Cohnhaus, D. W. 1988. Anticonvulsant and antiepileptogenic actions of MK-801 in the kindling and electroshock models. Neuropharmacology 27:563–568.

    PubMed  Google Scholar 

  66. Wilmot, C. A. 1989. Excitatory amino acid antagonists:behavioral and biochemical approaches for the development of new central neuron system therapeutic agents. Drug Development Res. 17:339–365.

    Google Scholar 

  67. Trout, J. J., Koenig, H., Goldstone, A. D., Iqbal, Z., and Siddiqui, F. 1993. NMDA receptor excitotoxicity involves activation of polyamine synthesis: protection by α-difluoromethylornithine. J. Neurochem. 60:352–355.

    PubMed  Google Scholar 

  68. McGurk, J. F., Bennett, M. V. L., and Zukin, R. S. 1990. Polyamines potentiate responses of N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Proc. Natl. Acad. Sci. USA 87:9971–9974.

    PubMed  Google Scholar 

  69. McCann, P., Pegg, A. E., and Sjoerdsma, A. (eds.) Inhibition to Polyamine Synthesis. Academic Press, San Diego, Ca, pp 1–371.

  70. Seiler, N., and Dezeuse, F. 1988. Polyamine transport in mammalian cells. Int. J. Biochem. 22:211–218.

    Google Scholar 

  71. Starke, K. A. 1981. Presynaptic Receptors. (Review) Annu. Rev. Pharmacol. Toxicol. 21:7–31.

    PubMed  Google Scholar 

  72. Jones, P. G. and Roberts, P. J. 1990. Ibotenate stimulates glutamate release from guinea pig cerebrocortical synaptosomes: inhibition by L-2-amino-4-phosphono-butyrate (L-AP4), Neurosci. Lett. 111:228–232.

    PubMed  Google Scholar 

  73. Shimizu, N., Shumin, D., Hori, T., and Domura, Y. 1990. Glutamate modulates dopamine release in the striatum as measured by brain microdialysis. Brain Res. Bull. 25:99–102.

    PubMed  Google Scholar 

  74. Koenig, H., Goldstone, A. D., Lu, C. Y., and Trout, J. J. 1991. Regulation of brain capillary permeability by neurotransmitters: Role of ODC/polyamine cascade. J. Cereb. Blood Flow and Metab. 11:S494.

    Google Scholar 

  75. Cotman, C. W., Bridges, R. J., Taube, J. S., Clark, A. S., Geddes, J. W., and Monaghan D. T. 1989. The role of the NMDA receptor in central neurons system plasticity and pathology. J. NIH Res. 1: 65–74.

    Google Scholar 

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  1. Department of Neurology, Northwestern University Medical School, 303 E. Chicago Avenue, Mail Code T-235, 60611-3008, Chicago, Illinois

    Farida Siddiqui & Zafar Iqbal

  2. Institute for Neuroscience, Northwestern University Medical School, 303 E. Chicago Avenue, Mail Code T-235, 60611-3008, Chicago, Illinois

    Zafar Iqbal

  3. Markey Center for Developmental Biology, Northwestern University Medical School, 60611-3008, Chicago, Illinois

    Zafar Iqbal

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Special issue dedicated to Dr. Sidney Ochs.

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Siddiqui, F., Iqbal, Z. Regulation of N-Methyl-d-aspartate receptor-mediated calcium transport and norepinephrine release in rat hippocampus synaptosomes by polyamines. Neurochem Res 19, 1421–1429 (1994). https://doi.org/10.1007/BF00972471

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