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Molecular Pharmacology

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Research ArticleArticle

Elevated Extracellular K+ Concentrations InhibitN-Methyl-d-Aspartate-Induced Ca2+ Influx and Excitotoxicity

Lech Kiedrowski
Molecular Pharmacology October 1999, 56 (4) 737-743;
Lech Kiedrowski
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This article has a correction. Please see:

  • Correction for vol. 56, p. 737 - December 01, 1999

Abstract

Although extracellular [K+] ([K+]E) is highly elevated during brain ischemia, in vitro studies aimed at explaining the mechanisms of excitotoxicity have been conducted at low [K+]E. Whether high [K+]E affects excitotoxicity has not been formally addressed. Therefore this study, using digital fluorescence microscopy, tested how the elevation of [K+]Efrom 5.6 to 60 mM affectsN-methyl-d-aspartate (NMDA)-induced Ca2+ and Na+ influx, plasma membrane (PM) potential, mitochondrial Ca2+ load, and viability of primary cultures of rat cerebellar granule cells. High [K+]E curtailed the NMDA-induced Ca2+ and Na+ influx and mitochondrial Ca2+ overload, and prevented neuronal death. Surprisingly, the inhibitory effect of high [K+]E on the NMDA-induced Ca2+ influx could not be linked to depolarization of the PM. Apparently, the PM of cerebellar granule cells exposed to NMDA was more depolarized at low than at high [K+]E, probably because the NMDA-induced Na+ influx was greatly enhanced when the extracellular [Na+]/[K+] ratio was increased. When this ratio was small, i.e., at high [K+]E, the NMDA-induced increase in cytoplasmic [Na+] was suppressed, preventing Ca2+ influx via the reverse operation of the Na+/Ca2+ exchanger, which may explain the inhibitory effect of high [K+]Eon NMDA-induced Ca2+ influx and excitotoxicity.

Footnotes

  • Send reprint requests to: Lech Kiedrowski, Ph.D., The Psychiatric Institute, 1601 W. Taylor St., Chicago, IL 60612. E-mail:lkiedr{at}psych.uic.edu

  • This work was supported by National Institutes of Health Grant NS 37390 and was presented in part in abstract form, Soc Neurosci Abst 895.4, 1997 and 300.5, 1998.

  • Abbreviations:
    PM
    plasma membrane
    CaDF
    electrochemical force for Ca2+ influx
    CGCs
    cerebellar granule cells
    CM
    conditioned medium
    DiBAC4(3)
    bis(1,3-dibutylbarbituric acid)trimethine oxonol
    Em
    plasma membrane potential
    F334/F380
    ratio of fluorescence intensities emitted after 334 nm and 380 nm excitation
    [K+]E and [Na+]E
    extracellular concentration of K+ and Na+, respectively
    [Na+]C
    [K+]C and [Ca2+]C, cytoplasmic concentration of Na+, K+, and Ca2+, respectively
    NaCaX
    Na+/Ca2+exchanger
    nF488
    normalized fluorescence intensity emitted after excitation at 488 nm
    NMDA
    N-methyl-d-aspartate
    SBFI
    Na+-binding benzofuran isophthalate
    R/NaCaX
    reverse operation of the Na+/Ca2+ exchanger
    • Received May 18, 1999.
    • Accepted June 29, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

Elevated Extracellular K+ Concentrations InhibitN-Methyl-d-Aspartate-Induced Ca2+ Influx and Excitotoxicity

Lech Kiedrowski
Molecular Pharmacology October 1, 1999, 56 (4) 737-743;

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Research ArticleArticle

Elevated Extracellular K+ Concentrations InhibitN-Methyl-d-Aspartate-Induced Ca2+ Influx and Excitotoxicity

Lech Kiedrowski
Molecular Pharmacology October 1, 1999, 56 (4) 737-743;
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