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Molecular Pharmacology

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Research ArticleArticle

Reverse Na+/Ca2+ Exchange Contributes to Glutamate-Induced Intracellular Ca2+ Concentration Increases in Cultured Rat Forebrain Neurons

Kari R. Hoyt, Stuart R. Arden, Elias Aizenman and Ian J. Reynolds
Molecular Pharmacology April 1998, 53 (4) 742-749; DOI: https://doi.org/10.1124/mol.53.4.742
Kari R. Hoyt
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Stuart R. Arden
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Elias Aizenman
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Ian J. Reynolds
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Abstract

Activation of ionotropic glutamate receptors causes increases in intracellular Ca2+ concentration ([Ca2+]i) and intracellular Na+concentration in neurons. It has been suggested that reversal of the plasma membrane Na+/Ca2+ exchanger (NCE) may account in part for the rise in [Ca2+]i. Recently, KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate) was reported to selectively inhibit the reverse mode of the NCE in non-neuronal cells. We investigated the effects of KB-R7943 on glutamate-stimulated increases in [Ca2+]i. In cultured rat forebrain neurons loaded with indo-1 acetoxymethyl ester, KB-R7943 inhibited the reverse mode of NCE (IC50 = 0.7 μm). When tested against kainate- (100 μm),N-methyl-d-aspartate- (30 μm), glutamate- (3 μm), or KCl- (50 mm) induced [Ca2+]i transients (15 sec, in the presence of Na+ and Ca2+), KB-R7943 inhibited these transients with IC50 values of 6.6, 8.2, 5.2, and 2.9 μm, respectively. [Ca2+]iincreases caused by a higher concentration of glutamate (100 μm) also were inhibited by KB-R7943 (10 μm). However, KB-R7943 had no effect on peak [Ca2+]i changes caused by prolonged application of glutamate and did not inhibit glutamate-induced neuronal injury. KB-R7943 did not inhibitN-methyl-d-aspartate- or kainate-induced whole-cell currents, nor did it substantially inhibit voltage-sensitive Ca2+ currents, excluding a direct inhibition of these ion channels. These results suggest that reverse NCE contributes to the immediate rise in [Ca2+]i resulting from glutamate receptor activation. However, reverse NCE becomes less important as the stimulus time is increased, and Ca2+ entry by this route is not critical for the expression of excitotoxic injury.

Footnotes

    • Received September 11, 1997.
    • Accepted December 12, 1997.
  • Send reprint requests to: Ian J. Reynolds, Ph.D., Department of Pharmacology, University of Pittsburgh School of Med., E1354 Biomedical Science Tower, Pittsburgh, PA 15261. E-mail:ijr{at}prophet.pharm.pitt.edu

  • This work was supported by National Institutes of Health Grants NS34138 and NS29365 and by the American Heart Association. S.R.A. is supported by National Institutes of Health Training Grant MH18273. I.J.R. is an Established Investigator of the American Heart Association.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (4)
Molecular Pharmacology
Vol. 53, Issue 4
1 Apr 1998
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Research ArticleArticle

Reverse Na+/Ca2+ Exchange Contributes to Glutamate-Induced Intracellular Ca2+ Concentration Increases in Cultured Rat Forebrain Neurons

Kari R. Hoyt, Stuart R. Arden, Elias Aizenman and Ian J. Reynolds
Molecular Pharmacology April 1, 1998, 53 (4) 742-749; DOI: https://doi.org/10.1124/mol.53.4.742

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Research ArticleArticle

Reverse Na+/Ca2+ Exchange Contributes to Glutamate-Induced Intracellular Ca2+ Concentration Increases in Cultured Rat Forebrain Neurons

Kari R. Hoyt, Stuart R. Arden, Elias Aizenman and Ian J. Reynolds
Molecular Pharmacology April 1, 1998, 53 (4) 742-749; DOI: https://doi.org/10.1124/mol.53.4.742
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