N-METHYL-D-ASPARTATE INDUCES A RAPID, REVERSIBLE, AND CALCIUM-DEPENDENT INTRACELLULAR ACIDOSIS IN CULTURED FETAL-RAT HIPPOCAMPAL-NEURONS

被引:100
作者
IRWIN, RP [1 ]
LIN, SZ [1 ]
LONG, RT [1 ]
PAUL, SM [1 ]
机构
[1] NIMH, CLIN NEUROSCI BRANCH, MOLEC PHARMACOL SECT, BETHESDA, MD 20892 USA
关键词
NMDA; RECEPTOR; INTRACELLULAR PH; ACIDOSIS; CALCIUM; NEUROTOXICITY;
D O I
10.1523/JNEUROSCI.14-03-01352.1994
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The ability of NMDA to alter intracellular pH (pH(i)) 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 mu M) results in a rapid, and in most cells reversible, reduction in pH(i), with full recovery to baseline pH(i) values taking several minutes following removal of NMDA. In contrast, little or no change in pH(i) 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 EC(50) of 39 mu M and E(max) (Delta pH) of -0.53. More prolonged exposure to NMDA(greater than or equal to 10 min) resulted in a more prolonged reduction in pH(i) 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-carboxypiperazi n-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 pH(i) indicating that Ca2+ influx may be required for the decrease in pH(i) induced by NMDA receptor activation. Finally, the NMDA-induced reduction in pH(i) 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 pH(i). The reduction in neuronal pH(i) induced by NMDA receptor activation may mediate some of the physiological and (or) pathophysiological actions of glutamate.
引用
收藏
页码:1352 / 1357
页数:6
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