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AMPA Receptor‐Mediated Excitotoxicity in Human NT2‐N Neurons Results from Loss of Intracellular Ca 2+ Homeostasis Following Marked Elevation of Intracellular Na +
Author(s) -
Itoh Takayuki,
Itoh Aki,
Horiuchi Kazumi,
Pleasure David
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71010112.x
Subject(s) - excitotoxicity , intracellular , ampa receptor , glutamate receptor , homeostasis , chemistry , receptor , microbiology and biotechnology , biophysics , endocrinology , biology , biochemistry
Human NT2‐N neurons express Ca 2+ ‐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 Ca 2+ levels ([Ca 2+ ] i ) was 1.9‐fold greater in the presence than in the absence of cyclothiazide, Ca 2+ 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 [Ca 2+ ] i rise. Transfer of the neurons to a 5 m M Na + medium after AMPA‐GluR activation accelerated the delayed [Ca 2+ ] 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 Ca 2+ , suggesting that Ca 2+ entry by reverse operation of Na + /Ca 2+ 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.