Reverse Na+/Ca2+ Exchange Contributes to Glutamate-Induced Intracellular Ca2+ Concentration Increases in Cultured Rat Forebrain Neurons
Activation of ionotropic glutamate receptors causes increases in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and intracellular Na + concentration in neurons. It has been suggested that reversal of the plasma membrane Na + /Ca 2+ exchanger (NCE) may account in part for the rise in [Ca 2+ ] i . Re...
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Veröffentlicht in: | Molecular pharmacology 1998-04, Vol.53 (4), p.742-749 |
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Zusammenfassung: | Activation of ionotropic glutamate receptors causes increases in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and intracellular Na + concentration in neurons. It has been suggested that reversal of the plasma membrane Na + /Ca 2+ exchanger (NCE) may account in part for the rise in [Ca 2+ ] 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 [Ca 2+ ] i . In cultured rat forebrain neurons loaded with indo-1 acetoxymethyl ester, KB-R7943 inhibited the reverse mode of NCE (IC 50 = 0.7 μ m ). When tested against kainate- (100 μ m ), N -methyl- d -aspartate- (30 μ m ), glutamate- (3 μ m ), or KCl- (50 m m ) induced [Ca 2+ ] i transients (15 sec, in the presence of Na + and Ca 2+ ), KB-R7943 inhibited these transients with IC 50 values of 6.6, 8.2, 5.2, and 2.9 μ m, respectively. [Ca 2+ ] i increases caused by a higher concentration of glutamate (100 μ m ) also were inhibited by KB-R7943 (10 μ m ). However, KB-R7943 had no effect on peak [Ca 2+ ] i changes caused by prolonged application of glutamate and did not inhibit glutamate-induced neuronal injury. KB-R7943 did
not inhibit N -methyl- d -aspartate- or kainate-induced whole-cell currents, nor did it substantially inhibit voltage-sensitive Ca 2+ currents, excluding a direct inhibition of these ion channels. These results suggest that reverse NCE contributes to the
immediate rise in [Ca 2+ ] i resulting from glutamate receptor activation. However, reverse NCE becomes less important as the stimulus time is increased,
and Ca 2+ entry by this route is not critical for the expression of excitotoxic injury. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.53.4.742 |