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Group on Cellular Neurobiology, Josai University, Sakado, Saitama
350-02, Japan (R.I., K.S.),
Fukui Research Institute, Ono
Pharmaceutical Company, Ltd., Mikuni-cho, Fukui 913, Japan (M.T.,
H.A.), and
Section on Molecular Neurobiology, Biological Psychiatry
Branch, National Institute of Mental Health, National Institutes of
Health, Bethesda, Maryland 20892 (D.-M.C.)
We have reported that overexpression of glyceraldehyde-3-phosphate
dehydrogenase (GAPDH; EC 1.2.1.12) is involved in age-induced apoptosis
of the cultured cerebellar granule cells that grow in a depolarizing
concentration (25 mM) of KCl. The present study was
undertaken to investigate whether GAPDH overexpression also occurs and
participates in apoptosis of the cerebellar granule cells that result
from switching the culturing conditions from high (25 mM)
to low (5 mM) concentrations of KCl. We found that exposure
of granule cells to low potassium (K+) for 24 hr induces
not only apoptosis but also necrotic damage. The latter is supported by
the morphological observations that a subpopulation of neurons showed
cell swelling, extensive cytoplasmic vacuolization, damaged
mitochondria, and apparently intact nuclei. Treatments with two
antisense but not sense oligodeoxyribonucleotides directed against
GAPDH attenuated low K+-induced neuronal death by
approximately 50%. Morphological inspection revealed that GAPDH
antisense oligonucleotides preferentially blocked low
K+-induced apoptosis with little or no effect on necrotic
damage. Similar to antisense oligonucleotides, actinomycin-D partially inhibited low K+-induced death of granule cells with a
predominant effect on apoptosis. In contrast, cycloheximide almost
completely blocked low K+-induced neuronal death and seemed
to prevent both apoptotic and necrotic damage. The levels of GAPDH mRNA
and protein were markedly increased in a time-dependent manner after
low K+ exposure. The overexpression of GAPDH mRNA and
protein was completely blocked by cycloheximide, actinomycin-D, and its
antisense but not sense oligonucleotides. Taken together, these results
lend credence to the view that exposure of cerebellar granule cells to
low K+ induces both apoptosis and necrosis and that only
the apoptotic component involves overexpression of GAPDH.
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