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Journal of Neuroscience, Vol 14, 1352-1357, Copyright © 1994 by Society for Neuroscience
N-methyl-D-aspartate induces a rapid, reversible, and calcium-dependent intracellular acidosis in cultured fetal rat hippocampal neurons
RP Irwin, SZ Lin, RT Long and SM Paul
Section on Molecular Pharmacology, National Institute of Mental Health, NIH, Bethesda, Maryland 20892.
The ability of NMDA to alter intracellular pH (pHi) was studied in fetal
rat hippocampal neurons and glia using the pH-sensitive fluorescent
indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6)- carboxyfluorescein (BCECF).
Brief exposure (60 sec) of hippocampal neurons to NMDA (2.5-250 microM)
results in a rapid, and in most cells reversible, reduction in pHi, with
full recovery to baseline pHi values taking several minutes following
removal of NMDA. In contrast, little or no change in pHi was observed in
glial cells exposed to these same concentrations of NMDA. The NMDA-induced
acidification of neurons was concentration and time dependent, with an EC50
of 39 microM and Emax (delta pH) of -0.53. More prolonged exposure to NMDA
(> or = 10 min) resulted in a more prolonged reduction in pHi values
over the ensuing 20 min observation period. The intracellular acidification
resulting from NMDA exposure of hippocampal neurons was blocked by the NMDA
receptor antagonist 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1- phosphonic
acid (CPP). Moreover, removal of extracellular Ca2+ eliminated both the
selective NMDA-induced elevation in [Ca2+]i and the reduction in pHi,
indicating that Ca2+ influx may be required for the decrease in pHi induced
by NMDA receptor activation. Finally, the NMDA- induced reduction in pHi
was not significantly attenuated when extracellular [H+] was decreased by
increasing extracellular pH to 8.0. The latter suggests that an
intracellular source of H+ is responsible for the NMDA-induced reduction in
neuronal pHi. The reduction in neuronal pHi induced by NMDA receptor
activation may mediate some of the physiological and (or)
pathophysiological actions of glutamate.
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