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Instrumental role of Na + in NMDA excitotoxicity in glucose‐deprived and depolarized cerebellar granule cells
Author(s) -
Czyż Aneta,
Baranauskas Gytis,
Kiedrowski Lech
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00851.x
Subject(s) - excitotoxicity , depolarization , ouabain , biophysics , nmda receptor , chemistry , extracellular , calcium , biochemistry , sodium , biology , receptor , organic chemistry
In glucose‐deprived cerebellar granule cells, substitution of extracellular Na + with Li + or Cs + prevented N ‐methyl‐ d ‐aspartate (NMDA)‐induced excitotoxicity. NMDA stimulated 45 Ca 2+ accumulation and ATP depletion in a Na‐dependent manner, and caused neuronal death, even if applied while Na,K‐ATPase was inhibited by 1 m m ouabain. The cells treated with NMDA in the presence of ouabain accumulated sizable 45 Ca 2+ load but most of them failed to elevate cytosolic [Ca 2+ ] upon mitochondrial depolarization. Na/Ca exchange inhibitor, KB‐R7943, inhibited Na‐dependent and NMDA‐induced 45 Ca 2+ accumulation but only if Na,K‐ATPase activity was compromised by ouabain. In cells energized by glucose and exposed to NMDA without ouabain, KB‐R7943 reduced NMDA‐elicited ionic currents by 19% but failed to inhibit 45 Ca 2+ accumulation. It appears that a large part of NMDA‐induced Ca 2+ influx in depolarized and glucose‐deprived cells is mediated by reverse Na/Ca exchange. A high level of reverse Na/Ca exchange operation is maintained by a sustained Na + influx via NMDA channels and depolarization of the plasma membrane. In cells energized by glucose, however, most Ca 2+ enters directly via NMDA channels because Na,K‐ATPase regenerating Na + and K + concentration gradients prevents Na/Ca exchange reversal. Since under these conditions Na/Ca exchange extrudes Ca 2+ , its inhibition destabilizes Ca 2+ homeostasis.