Abstract
Human NT2-N neurons express Ca2+-permeable α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid glutamate receptors (AMPA-GluRs) and become vulnerable to excitotoxicity when AMPA-GluR desensitization is blocked with cyclothiazide. Although the initial increase in intracellular Ca2+ levels ([Ca2+](i)) was 1.9-fold greater in the presence than in the absence of cyclothiazide, Ca2+ entry via AMPA-GluRs in an early phase of the exposure was not necessary to elicit excitotoxicity in these neurons. Rather, subsequent necrosis was caused by a >40-fold rise in [Na+](i), which induced a delayed [Ca2+](i) rise. Transfer of the neurons to a 5 mM Na+ medium after AMPA-GluR activation accelerated the delayed [Ca2+](i) rise and intensified excitotoxicity. Low-Na+ medium-enhanced excitotoxicity was partially blocked by amiloride or dizocilpine (MK-801), and completely blocked by removal of extracellular Ca2+, suggesting that Ca2+ entry by reverse operation of Na+/Ca2+ exchangers and via NMDA glutamate receptors was responsible for the neuronal death after excessive Na+ loading. Our results serve to emphasize the central role of neuronal Na+ loading in AMPA- GluR-mediated excitotoxicity in human neurons.
Original language | English (US) |
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Pages (from-to) | 112-124 |
Number of pages | 13 |
Journal | Journal of Neurochemistry |
Volume | 71 |
Issue number | 1 |
State | Published - Jul 1998 |
Externally published | Yes |
Keywords
- α-Amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptor desensitization
- Calcium
- Glutamate excitotoxicity
- Human neuron
- Sodium
- Sodium-calcium exchange
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience