Tags

Type your tag names separated by a space and hit enter

Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons.
Mol Pharmacol. 1998 Apr; 53(4):742-9.MP

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 microM). When tested against kainate- (100 microM), N-methyl-D-aspartate- (30 microM), glutamate- (3 microM), 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 microM, respectively. [Ca2+]i increases caused by a higher concentration of glutamate (100 microM) also were inhibited by KB-R7943 (10 microM). 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.

Authors+Show Affiliations

Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9547366

Citation

Hoyt, K R., et al. "Reverse Na+/Ca2+ Exchange Contributes to Glutamate-induced Intracellular Ca2+ Concentration Increases in Cultured Rat Forebrain Neurons." Molecular Pharmacology, vol. 53, no. 4, 1998, pp. 742-9.
Hoyt KR, Arden SR, Aizenman E, et al. Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons. Mol Pharmacol. 1998;53(4):742-9.
Hoyt, K. R., Arden, S. R., Aizenman, E., & Reynolds, I. J. (1998). Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons. Molecular Pharmacology, 53(4), 742-9.
Hoyt KR, et al. Reverse Na+/Ca2+ Exchange Contributes to Glutamate-induced Intracellular Ca2+ Concentration Increases in Cultured Rat Forebrain Neurons. Mol Pharmacol. 1998;53(4):742-9. PubMed PMID: 9547366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reverse Na+/Ca2+ exchange contributes to glutamate-induced intracellular Ca2+ concentration increases in cultured rat forebrain neurons. AU - Hoyt,K R, AU - Arden,S R, AU - Aizenman,E, AU - Reynolds,I J, PY - 1998/5/9/pubmed PY - 1998/5/9/medline PY - 1998/5/9/entrez SP - 742 EP - 9 JF - Molecular pharmacology JO - Mol Pharmacol VL - 53 IS - 4 N2 - 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 microM). When tested against kainate- (100 microM), N-methyl-D-aspartate- (30 microM), glutamate- (3 microM), 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 microM, respectively. [Ca2+]i increases caused by a higher concentration of glutamate (100 microM) also were inhibited by KB-R7943 (10 microM). 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/9547366/Reverse_Na+/Ca2+_exchange_contributes_to_glutamate_induced_intracellular_Ca2+_concentration_increases_in_cultured_rat_forebrain_neurons_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9547366 DB - PRIME DP - Unbound Medicine ER -