Elevated extracellular K+ concentrations inhibit N-methyl-D-aspartate-induced Ca2+ influx and excitotoxicity

Although extracellular [K+] ([K+](E)) is highly elevated during brain ische mia, in vitro studies aimed at explaining the mechanisms of excitotoxicity have been conducted at low [K+](E). Whether high [K+](E) affects excitotoxi city has not been formally addressed. Therefore this study, using digital f luorescence microscopy, tested how the elevation of [K+](E) from 5.6 to 60 mM affects N-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-i nduced Ca2+ and Na+ influx and mitochondrial Ca2+ overload, and prevented n euronal death. Surprisingly, the inhibitory effect of high [K+](E) on the N MDA-induced Ca2+ influx could not be linked to depolarization of the PM. Ap parently, the PM of cerebellar granule cells exposed to NMDA was more depol arized at low than at high [K+](E), probably because the NMDA-induced Na+ i nflux was greatly enhanced when the extracellular [Na+]/[K+] ratio was incr eased. When this ratio was small, i.e., at high [K+](E), the NMDA-induced i ncrease in cytoplasmic [Na+] was suppressed, preventing Ca2+ influx via the reverse operation of the Na+/ Ca2+ exchanger, which may explain the inhibi tory effect of high [K+](E) on NMDA-induced Ca2+ influx and excitotoxicity.