A role for Na+-dependent Ca2+ extrusion in protection against neuronal excitotoxicity

The hypothesis that Na+-dependent calcium extrusion is important in protecting against neuronal excitotoxicity was tested. In cocultures of embryonic rat hippocampal neurons and mouse neuroblastoma hybrid (NCB-20) cells, calcium ionophore A23187 (1 microM) or high levels of extracellular K+ killed hippocampal neurons selectively, leaving NCB-20 cells unscathed. Hippocampal neurons showed large, sustained rises in intracellular calcium in response to A23187 or K+, whereas NCB-20 cells showed only transient calcium responses. The ability of NCB-20 cells to reduce the calcium load and to survive exposure to A23187 or K+ were dependent on extracellular Na+, suggesting that an active Na+/Ca2+ exchange mechanism was important in protecting against cell death. Finally, removal of extracellular Na+ reduced the threshold for glutamate neurotoxicity in hippocampal neurons, demonstrating the importance of Na+/Ca2+ exchange in protecting against excitotoxicity. Taken together, these findings suggest that differences in cell calcium-regulating systems may determine whether a neuron lives or degenerates in the face of an excitatory challenge.