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) |
|---|---|
| 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 |
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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
Cite this
AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+ . / Ito, Takayuki; Itoh, Aki; Horiuchi, Kazumi; Pleasure, David E.
In: Journal of Neurochemistry, Vol. 71, No. 1, 07.1998, p. 112-124.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+
AU - Ito, Takayuki
AU - Itoh, Aki
AU - Horiuchi, Kazumi
AU - Pleasure, David E
PY - 1998/7
Y1 - 1998/7
N2 - 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.
AB - 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.
KW - α-Amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptor desensitization
KW - Calcium
KW - Glutamate excitotoxicity
KW - Human neuron
KW - Sodium
KW - Sodium-calcium exchange
UR - http://www.scopus.com/inward/record.url?scp=0031814379&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031814379&partnerID=8YFLogxK
M3 - Article
C2 - 9648857
AN - SCOPUS:0031814379
VL - 71
SP - 112
EP - 124
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 1
ER -