AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+

Takayuki Ito, Aki Itoh, Kazumi Horiuchi, David E Pleasure

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)112-124
Number of pages13
JournalJournal of Neurochemistry
Volume71
Issue number1
StatePublished - Jul 1998
Externally publishedYes

Fingerprint

AMPA Receptors
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Neurons
Glutamate Receptors
Homeostasis
Dizocilpine Maleate
Amiloride
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Necrosis
Chemical activation
bucide
propionic acid
cyclothiazide

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 journalArticle

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