Role of Na+/Ca2+ exchange in regulation of neuronal Ca2+ homeostasis requires re-evaluation

In cultured rat cerebellar granule cells an inhibition of plasma membrane Na+/Ca2+ exchange by removal of external Na+ (replacement with NMDG) caused an increase in [Ca2+](i) at rest and a considerable delay in [Ca2+](i) recovery from Glu-imposed [Ca2+](i) load. These effects did not result from Ca2+ influx through reversed Na+/Ca2+ exchange since they were readily abolished or prevented by using the NR IDA receptor inhibitor AP-5 (100 mu M) or the NMDA channel blocker memantine (25-50 mu M). The effect of Na+/NMDG replacement could be enhanced by: (1) an increase in cytoplasmic Na+ concentration by monensin pretreatment of neurons; (2) external alkalinity, pH 8.5; (3) blockade of the mitochondrial Ca2+ uptake with antimycin plus oligomycin. Analysis of the data obtained led us to conclude that all the changes in [Ca2+](i) caused by Na+/NMDG replacement are mainly due to a release of endogenous Glu (reversed Glu uptake) and a subsequent Ca2+ influx through NMDA receptor-mediated channels. (C) 1998 Federation of European Biochemical Societies.