Instrumental role of Na+ in NMDA excitotoxicity in glucose‐deprived and depolarized cerebellar granule cells

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Abstract
In glucose‐deprived cerebellar granule cells, substitution of extracellular Na+ with Li+ or Cs+ prevented N‐methyl‐d‐aspartate (NMDA)‐induced excitotoxicity. NMDA stimulated 45Ca2+ accumulation and ATP depletion in a Na‐dependent manner, and caused neuronal death, even if applied while Na,K‐ATPase was inhibited by 1 mm ouabain. The cells treated with NMDA in the presence of ouabain accumulated sizable 45Ca2+ load but most of them failed to elevate cytosolic [Ca2+] upon mitochondrial depolarization. Na/Ca exchange inhibitor, KB‐R7943, inhibited Na‐dependent and NMDA‐induced 45Ca2+ 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 45Ca2+ accumulation. It appears that a large part of NMDA‐induced Ca2+ 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 Ca2+ 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 Ca2+, its inhibition destabilizes Ca2+ homeostasis.