RT Journal Article
SR Electronic
T1 N-methyl-d-aspartate Excitotoxicity: Relationships among Plasma Membrane Potential, Na+/Ca2+ Exchange, Mitochondrial Ca2+ Overload, and Cytoplasmic Concentrations of Ca2+, H+, and K+
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 619
OP 632
DO 10.1124/mol.56.3.619
VO 56
IS 3
A1 Kiedrowski, Lech
YR 1999
UL http://molpharm.aspetjournals.org/content/56/3/619.abstract
AB A high cytoplasmic Na+ concentration may contribute to N-methyl-d-aspartate (NMDA)-induced excitotoxicity by promoting Ca2+ influx via reverse operation of the Na+/Ca2+ exchanger (NaCaX), but may simultaneously decrease the electrochemical Ca2+driving force by depolarizing the plasma membrane (PM). Digital fluorescence microscopy was used to compare the effects of Na+ versus ions that do not support the NaCaX operation, i.e., N-methyl-d-glucamine+ or Li+, on: PM potential; cytoplasmic concentrations of Ca2+, H+, and K+; mitochondrial Ca2+ storage; and viability of primary cultures of cerebellar granule cells exposed to NMDA receptor agonists. In the presence of Na+ or Li+, NMDA depolarized the PM and decreased cytoplasmic pH (pHC); in the presence of Li+, Ca2+ influx was reduced, mitochondrial Ca2+ overload did not occur, and the cytoplasm became more acidified than in the presence of Na+. In the presence ofN-methyl-d-glucamine+, NMDA instantly hyperpolarized the PM, but further changes in PM potential and pHC were Ca-dependent. In the absence of Ca2+, hyperpolarization persisted, pHC was decreasing very slowly, K+ was retained in the cytoplasm, and cerebellar granule cells survived the challenge; in the presence of Ca2+, pHC dropped rapidly, the K+concentration gradient across the PM began to collapse as the PM began to depolarize, and Ca2+ influx and excitotoxicity greatly increased. These results indicate that the dominant, very likely excitotoxic, component of NMDA-induced Ca2+ influx is mediated by reverse NaCaX and that direct Ca2+ influx via NMDA channels is curtailed by Na-dependent PM depolarization.