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.
Mattson
M P
MP
Sanders-Brown Center on Aging, University of Kentucky Medical Center, Lexington 40536.
Guthrie
P B
PB
Kater
S B
SB
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D005971:Glutamates; D000001:Calcimycin; D018698:Glutamic Acid; D012964:Sodium; D011188:Potassium; D002118:Calcium