Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate excitotoxicity in the oligodendroglial lineage.
We demonstrate by reverse transcriptase-polymerase chain reaction and Southern blotting that an immortalized rat oligodendroglial cell line (CG-4) expresses the non-N-methyl-D-aspartate (non-NMDA) glutamate receptor (GluR) genes GluR2-7, KA-1, and KA-2 and that nonimmortalized cells of the rat oligodendroglial lineage express the GluR1-3, GluR5-7, KA-1, and KA-2 genes. Lactic dehydrogenase release assays show that both immortalized and nonimmortalized cells of the oligodendroglial lineage are damaged by a 24-h exposure to 500 microM kainate or 5 mM L-glutamate, but not by a 24-h exposure to up to 10 mM alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). Damage is prevented by the non-NMDA GluR channel inhibitor 6-cyano-7-nitroquinoxaline-2,3-dione and is also averted if Ca2+ is removed from the culture medium. Cyclothiazide, which blocks desensitization of AMPA-preferring GluRs, increases cytotoxicity of kainate as well as inducing toxicity of AMPA. We conclude that cells of the oligodendroglial lineage express a population of AMPA-preferring and possibly also kainate-preferring GluR channels that are capable of mediating Ca(2+)-dependent excitotoxicity and that AMPA-induced cytotoxicity is blocked by desensitization of AMPA-preferring GluRs.
Yoshioka
A
A
Children's Hospital of Philadelphia, PA 19104, USA.
Hardy
M
M
Younkin
D P
DP
Grinspan
J B
JB
Stern
J L
JL
Pleasure
D
D
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015870:Gene Expression; D018698:Glutamic Acid / Q000494:pharmacology; D007473:Ion Channels / Q000235:genetics; D007608:Kainic Acid / Q000494:pharmacology; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects*; D015345:Oligonucleotide Probes / Q000235:genetics; D016133:Polymerase Chain Reaction; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism; D014158:Transcription, Genetic; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D007473:Ion Channels; D009498:Neurotoxins; D015345:Oligonucleotide Probes; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid