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Vol. 53, Issue 4, 742-749, April 1998
Departments of
Pharmacology (K.R.H., I.J.R.) and
Neurobiology
(S.R.A., E.A.), University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 15261
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+]i
increases 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 inhibit
N-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.
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