Abstract
Striatal and cortical neurons containing NADPH-diaphorase [NADPH-d(+)] are highly vulnerable to excitotoxicity that is induced by activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- or kainate-sensitive glutamate receptors. This has been attributed to Ca2+ entry through AMPA/kainate receptors in NADPH-d(+) neurons. In this study, we applied single cell RT-PCR technique to test the hypothesis that differences in levels and processing of the GluR2 subunit would contribute to the selective vulnerability of NADPH-d(+) neurons to AMPA. The nested PCR specific for GluR1-GluR4 showed that rat striatal NADPH-d(+) neurons expressed twice as much GluR1 mRNA as NADPH-d(-) neurons did. The percentage of RNA editing at the Q/R site of GluR2 was 46% in NADPH-d(+) neurons and 92% in NADPH-d(-) neurons. These results suggest that the unedited expression of GluR2 and the reduced ratio of GluR2/GluR1 render NADPH-d(+) neurons highly sensitive to Ca2+-mediated AMPA neurotoxicity. In support of this, most NADPH-d(+) neurons exposed to 100 microM AMPA showed Co2+ uptake and survived AMPA challenge only in the absence of extracellular Ca2+.
Copyright 2001 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Cell Membrane Permeability / drug effects
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Cell Membrane Permeability / physiology
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cobalt / pharmacology
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Dose-Response Relationship, Drug
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Excitatory Amino Acid Agonists / pharmacology
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Fetus
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Gene Expression / drug effects
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Gene Expression / physiology
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NADPH Dehydrogenase / metabolism*
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Neostriatum / cytology
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Neostriatum / drug effects
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Neostriatum / metabolism
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Neurotoxins / pharmacology*
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RNA Editing / drug effects
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RNA Editing / physiology*
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism*
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Rats
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Receptors, AMPA / agonists
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Receptors, AMPA / genetics*
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Receptors, AMPA / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Excitatory Amino Acid Agonists
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Neurotoxins
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RNA, Messenger
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Receptors, AMPA
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Cobalt
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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NADPH Dehydrogenase
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glutamate receptor ionotropic, AMPA 2
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Calcium
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glutamate receptor ionotropic, AMPA 1