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. 1993 May;109(1):107–112. doi: 10.1111/j.1476-5381.1993.tb13538.x

Effects of pH on the actions of dizocilpine at the N-methyl-D-aspartate receptor complex.

S Rajdev 1, I J Reynolds 1
PMCID: PMC2175603  PMID: 8495234

Abstract

1. The effects of varying pH from 6.5 to 7.4 and 8.0 on the actions of dizocilpine (MK801) on the N-methyl-D-aspartate (NMDA) receptor were investigated by use of a [3H]-dizocilpine binding assay and NMDA-induced intracellular free Ca2+ ([Ca2+]i) increases in cultured forebrain neurones. 2. Increasing pH from 6.5 to 8.0 significantly increased the rate of association and dissociation of [3H]-dizocilpine. The association process was better described by two rate constants under each condition, while only dissociation of [3H]-dizocilpine at pH 8.0 required two rate constants adequately to describe the curve. Equilibrium affinity of [3H]-dizocilpine was not altered by changing pH from 6.5 to 8.0. 3. NMDA and glycine together increased [Ca2+]i measured by fura-2 microspectrofluorimetry in single cultured neurones from rat forebrain. Compared to control response measured at pH 7.4, the combined effects of NMDA and glycine were reduced to 38.9% of control values by lowering pH to 6.5 and increased to 148.9% by raising pH to 8.0. 4. Dizocilpine (200 nM) effectively reversed increases in [Ca2+]i produced by NMDA together with glycine. The rate of reversal produced by this concentration of dizocilpine was considerably slower than that required for cells to recover to baseline following agonist removal. The rate at which dizocilpine reversed NMDA- and glycine-induced [Ca2+]i increases was not altered by raising pH from 6.5 to 8.0. 5. These data support the hypothesis that the rates associated with [3H]-dizocilpine binding are controlled by the level of activation of the receptor. In addition, these data confirm previous findings that NMDA responses are sensitive to small changes in pH.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Aizenman E., Hartnett K. A., Reynolds I. J. Oxygen free radicals regulate NMDA receptor function via a redox modulatory site. Neuron. 1990 Dec;5(6):841–846. doi: 10.1016/0896-6273(90)90343-e. [DOI] [PubMed] [Google Scholar]
  2. Anis N. A., Berry S. C., Burton N. R., Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983 Jun;79(2):565–575. doi: 10.1111/j.1476-5381.1983.tb11031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bonhaus D. W., McNamara J. O. N-methyl-D-aspartate receptor regulation of uncompetitive antagonist binding in rat brain membranes: kinetic analysis. Mol Pharmacol. 1988 Sep;34(3):250–255. [PubMed] [Google Scholar]
  4. Davies S. N., Martin D., Millar J. D., Aram J. A., Church J., Lodge D. Differences in results from in vivo and in vitro studies on the use-dependency of N-methylaspartate antagonism by MK-801 and other phencyclidine receptor ligands. Eur J Pharmacol. 1988 Jan 12;145(2):141–151. doi: 10.1016/0014-2999(88)90225-7. [DOI] [PubMed] [Google Scholar]
  5. Foster A. C., Wong E. H. The novel anticonvulsant MK-801 binds to the activated state of the N-methyl-D-aspartate receptor in rat brain. Br J Pharmacol. 1987 Jun;91(2):403–409. doi: 10.1111/j.1476-5381.1987.tb10295.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  7. Honey C. R., Miljkovic Z., MacDonald J. F. Ketamine and phencyclidine cause a voltage-dependent block of responses to L-aspartic acid. Neurosci Lett. 1985 Oct 24;61(1-2):135–139. doi: 10.1016/0304-3940(85)90414-8. [DOI] [PubMed] [Google Scholar]
  8. Huettner J. E., Bean B. P. Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1307–1311. doi: 10.1073/pnas.85.4.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Javitt D. C., Zukin S. R. Biexponential kinetics of [3H]MK-801 binding: evidence for access to closed and open N-methyl-D-aspartate receptor channels. Mol Pharmacol. 1989 Apr;35(4):387–393. [PubMed] [Google Scholar]
  10. Johnson J. W., Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature. 1987 Feb 5;325(6104):529–531. doi: 10.1038/325529a0. [DOI] [PubMed] [Google Scholar]
  11. Kloog Y., Haring R., Sokolovsky M. Kinetic characterization of the phencyclidine-N-methyl-D-aspartate receptor interaction: evidence for a steric blockade of the channel. Biochemistry. 1988 Feb 9;27(3):843–848. doi: 10.1021/bi00403a001. [DOI] [PubMed] [Google Scholar]
  12. Loo P., Braunwalder A., Lehmann J., Williams M. Radioligand binding to central phencyclidine recognition sites is dependent on excitatory amino acid receptor agonists. Eur J Pharmacol. 1986 Apr 29;123(3):467–468. doi: 10.1016/0014-2999(86)90726-0. [DOI] [PubMed] [Google Scholar]
  13. MacDermott A. B., Mayer M. L., Westbrook G. L., Smith S. J., Barker J. L. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. 1986 May 29-Jun 4Nature. 321(6069):519–522. doi: 10.1038/321519a0. [DOI] [PubMed] [Google Scholar]
  14. MacDonald J. F., Miljkovic Z., Pennefather P. Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. J Neurophysiol. 1987 Aug;58(2):251–266. doi: 10.1152/jn.1987.58.2.251. [DOI] [PubMed] [Google Scholar]
  15. MacDonald J. F., Nowak L. M. Mechanisms of blockade of excitatory amino acid receptor channels. Trends Pharmacol Sci. 1990 Apr;11(4):167–172. doi: 10.1016/0165-6147(90)90070-O. [DOI] [PubMed] [Google Scholar]
  16. Mayer M. L., Westbrook G. L., Guthrie P. B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984 May 17;309(5965):261–263. doi: 10.1038/309261a0. [DOI] [PubMed] [Google Scholar]
  17. Murphy S. N., Thayer S. A., Miller R. J. The effects of excitatory amino acids on intracellular calcium in single mouse striatal neurons in vitro. J Neurosci. 1987 Dec;7(12):4145–4158. doi: 10.1523/JNEUROSCI.07-12-04145.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nowak L., Bregestovski P., Ascher P., Herbet A., Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984 Feb 2;307(5950):462–465. doi: 10.1038/307462a0. [DOI] [PubMed] [Google Scholar]
  19. Peters S., Koh J., Choi D. W. Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science. 1987 May 1;236(4801):589–593. doi: 10.1126/science.2883728. [DOI] [PubMed] [Google Scholar]
  20. Ransom R. W., Stec N. L. Cooperative modulation of [3H]MK-801 binding to the N-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine, and polyamines. J Neurochem. 1988 Sep;51(3):830–836. doi: 10.1111/j.1471-4159.1988.tb01818.x. [DOI] [PubMed] [Google Scholar]
  21. Reynolds I. J. 1,5-(Diethylamino)piperidine, a novel spermidine analogue that more specifically activates the N-methyl-D-aspartate receptor-associated polyamine site. Mol Pharmacol. 1992 Jun;41(6):989–992. [PubMed] [Google Scholar]
  22. Reynolds I. J., Aizenman E. Pentamidine is an N-methyl-D-aspartate receptor antagonist and is neuroprotective in vitro. J Neurosci. 1992 Mar;12(3):970–975. doi: 10.1523/JNEUROSCI.12-03-00970.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Reynolds I. J. Arcaine uncovers dual interactions of polyamines with the N-methyl-D-aspartate receptor. J Pharmacol Exp Ther. 1990 Dec;255(3):1001–1007. [PubMed] [Google Scholar]
  24. Reynolds I. J., Miller R. J. Ifenprodil is a novel type of N-methyl-D-aspartate receptor antagonist: interaction with polyamines. Mol Pharmacol. 1989 Nov;36(5):758–765. [PubMed] [Google Scholar]
  25. Reynolds I. J., Miller R. J. Multiple sites for the regulation of the N-methyl-D-aspartate receptor. Mol Pharmacol. 1988 Jun;33(6):581–584. [PubMed] [Google Scholar]
  26. Reynolds I. J., Miller R. J. [3H]MK801 binding to the NMDA receptor/ionophore complex is regulated by divalent cations: evidence for multiple regulatory sites. Eur J Pharmacol. 1988 Jun 22;151(1):103–112. doi: 10.1016/0014-2999(88)90697-8. [DOI] [PubMed] [Google Scholar]
  27. Reynolds I. J., Palmer A. M. Regional variations in [3H]MK801 binding to rat brain N-methyl-D-aspartate receptors. J Neurochem. 1991 May;56(5):1731–1740. doi: 10.1111/j.1471-4159.1991.tb02074.x. [DOI] [PubMed] [Google Scholar]
  28. Sacaan A. I., Johnson K. M. Characterization of the stimulatory and inhibitory effects of polyamines on [3H]N-(1-[thienyl]cyclohexyl) piperidine binding to the N-methyl-D-aspartate receptor ionophore complex. Mol Pharmacol. 1990 Apr;37(4):572–577. [PubMed] [Google Scholar]
  29. Starmer C. F., Packer D. L., Grant A. O. Ligand binding to transiently accessible sites: mechanisms for varying apparent binding rates. J Theor Biol. 1987 Feb 7;124(3):335–341. doi: 10.1016/s0022-5193(87)80120-0. [DOI] [PubMed] [Google Scholar]
  30. Takadera T., Shimada Y., Mohri T. Extracellular pH modulates N-methyl-D-aspartate receptor-mediated neurotoxicity and calcium accumulation in rat cortical cultures. Brain Res. 1992 Feb 14;572(1-2):126–131. doi: 10.1016/0006-8993(92)90460-q. [DOI] [PubMed] [Google Scholar]
  31. Tang C. M., Dichter M., Morad M. Modulation of the N-methyl-D-aspartate channel by extracellular H+. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6445–6449. doi: 10.1073/pnas.87.16.6445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Traynelis S. F., Cull-Candy S. G. Pharmacological properties and H+ sensitivity of excitatory amino acid receptor channels in rat cerebellar granule neurones. J Physiol. 1991 Feb;433:727–763. doi: 10.1113/jphysiol.1991.sp018453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Traynelis S. F., Cull-Candy S. G. Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons. Nature. 1990 May 24;345(6273):347–350. doi: 10.1038/345347a0. [DOI] [PubMed] [Google Scholar]
  34. Westbrook G. L., Mayer M. L. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature. 1987 Aug 13;328(6131):640–643. doi: 10.1038/328640a0. [DOI] [PubMed] [Google Scholar]
  35. Williams K., Dawson V. L., Romano C., Dichter M. A., Molinoff P. B. Characterization of polyamines having agonist, antagonist, and inverse agonist effects at the polyamine recognition site of the NMDA receptor. Neuron. 1990 Aug;5(2):199–208. doi: 10.1016/0896-6273(90)90309-4. [DOI] [PubMed] [Google Scholar]
  36. Wong E. H., Kemp J. A., Priestley T., Knight A. R., Woodruff G. N., Iversen L. L. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104–7108. doi: 10.1073/pnas.83.18.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wu F. S., Gibbs T. T., Farb D. H. Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol Pharmacol. 1991 Sep;40(3):333–336. [PubMed] [Google Scholar]

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