AMPA Receptor-Mediated Excitotoxicity in Human NT2-N Neurons Results from Loss of Intracellular Ca2+ Homeostasis Following Marked Elevation of Intracellular Na+ |
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Authors: | Takayuki Itoh Aki Itoh Kazumi Horiuchi David Pleasure |
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Institution: | Division of Neurology and; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A. |
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Abstract: | 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 m M 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. |
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Keywords: | Human neuron Glutamate excitotoxicity α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor desensitization Calcium Sodium Sodium-calcium exchange |
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