Abstract

Although extracellular [K⁺] ([K⁺]_E) is highly elevated during brain ischemia, in vitro studies aimed at explaining the mechanisms of excitotoxicity have been conducted at low [K⁺]_E. Whether high [K⁺]_E affects excitotoxicity has not been formally addressed. Therefore this study, using digital fluorescence microscopy, tested how the elevation of [K⁺]_Efrom 5.6 to 60 mM affectsN-methyl-d-aspartate (NMDA)-induced Ca²⁺ and Na⁺ influx, plasma membrane (PM) potential, mitochondrial Ca²⁺ load, and viability of primary cultures of rat cerebellar granule cells. High [K⁺]_E curtailed the NMDA-induced Ca²⁺ and Na⁺ influx and mitochondrial Ca²⁺ overload, and prevented neuronal death. Surprisingly, the inhibitory effect of high [K⁺]_E on the NMDA-induced Ca²⁺ influx could not be linked to depolarization of the PM. Apparently, the PM of cerebellar granule cells exposed to NMDA was more depolarized at low than at high [K⁺]_E, probably because the NMDA-induced Na⁺ influx was greatly enhanced when the extracellular [Na⁺]/[K⁺] ratio was increased. When this ratio was small, i.e., at high [K⁺]_E, the NMDA-induced increase in cytoplasmic [Na⁺] was suppressed, preventing Ca²⁺ influx via the reverse operation of the Na⁺/Ca²⁺ exchanger, which may explain the inhibitory effect of high [K⁺]_Eon NMDA-induced Ca²⁺ influx and excitotoxicity.