PT  - JOURNAL ARTICLE
AU  - Kiedrowski, Lech
TI  - &lt;em&gt;N-&lt;/em&gt;methyl-&lt;span class=&quot;sc&quot;&gt;d&lt;/span&gt;-aspartate Excitotoxicity: Relationships among Plasma Membrane Potential, Na&lt;sup&gt;+&lt;/sup&gt;/Ca&lt;sup&gt;2+&lt;/sup&gt; Exchange, Mitochondrial Ca&lt;sup&gt;2+&lt;/sup&gt; Overload, and Cytoplasmic Concentrations of Ca&lt;sup&gt;2+&lt;/sup&gt;, H&lt;sup&gt;+&lt;/sup&gt;, and K&lt;sup&gt;+&lt;/sup&gt;
AID  - 10.1124/mol.56.3.619
DP  - 1999 Sep 01
TA  - Molecular Pharmacology
PG  - 619--632
VI  - 56
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/56/3/619.short
4100  - http://molpharm.aspetjournals.org/content/56/3/619.full
SO  - Mol Pharmacol1999 Sep 01; 56
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.