N-methyl-D-aspartate excitotoxicity: relationships among plasma membrane potential, Na(+)/Ca(2+) exchange, mitochondrial Ca(2+) overload, and cytoplasmic concentrations of Ca(2+), H(+), and K(+).
A high cytoplasmic Na(+) concentration may contribute to N-methyl-D-aspartate (NMDA)-induced excitotoxicity by promoting Ca(2+) influx via reverse operation of the Na(+)/Ca(2+) exchanger (NaCaX), but may simultaneously decrease the electrochemical Ca(2+) 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 Ca(2+), H(+), and K(+); mitochondrial Ca(2+) 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 (pH(C)); in the presence of Li(+), Ca(2+) influx was reduced, mitochondrial Ca(2+) overload did not occur, and the cytoplasm became more acidified than in the presence of Na(+). In the presence of N-methyl-D-glucamine(+), NMDA instantly hyperpolarized the PM, but further changes in PM potential and pH(C) were Ca-dependent. In the absence of Ca(2+), hyperpolarization persisted, pH(C) was decreasing very slowly, K(+) was retained in the cytoplasm, and cerebellar granule cells survived the challenge; in the presence of Ca(2+), pH(C) dropped rapidly, the K(+) concentration gradient across the PM began to collapse as the PM began to depolarize, and Ca(2+) influx and excitotoxicity greatly increased. These results indicate that the dominant, very likely excitotoxic, component of NMDA-induced Ca(2+) influx is mediated by reverse NaCaX and that direct Ca(2+) influx via NMDA channels is curtailed by Na-dependent PM depolarization.
Kiedrowski
L
L
The Psychiatric Institute, Departments of Psychiatry and Pharmacology, College of Medicine, The University of Illinois at Chicago, Chicago, Illinois, USA. lkiedr@psych.uic.edu
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005942:Gluconates / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008536:Meglumine / Q000031:analogs & derivatives / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; D005942:Gluconates; D011522:Protons; D019831:Sodium-Calcium Exchanger; C051643:N-methylglucamine gluconate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D008536:Meglumine; D012964:Sodium; D011188:Potassium; D002118:Calcium