Vol. 56, Issue 4, 737-743, October 1999

Elevated Extracellular K⁺ Concentrations Inhibit N-Methyl-D-Aspartate-Induced Ca²⁺ Influx and Excitotoxicity

Lech Kiedrowski

The Psychiatric Institute, Departments of Psychiatry and Pharmacology, College of Medicine, The University of Illinois at Chicago, Chicago, Illinois

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⁺]_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-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⁺]_E on NMDA-induced Ca²⁺ influx and excitotoxicity.