Domoic acid neurotoxicity in cultured cerebellar granule neurons is controlled preferentially by the NMDA receptor Ca2+ influx pathway

被引:64
作者
Berman, FW [1 ]
Lepage, KT [1 ]
Murray, TF [1 ]
机构
[1] Univ Georgia, Coll Vet Med, Dept Physiol & Pharmacol, Athens, GA 30602 USA
关键词
domoic acid; excitotoxicity; calcium; NMDA receptor; voltage-sensitive calcium channel; Na+/Ca2+ exchanger;
D O I
10.1016/S0006-8993(01)03221-8
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We have monitored real-time alterations in [Ca2+](i) in fluo-3-loaded cerebellar granule neurons exposed to domoate, and ascertained the influence of pharmacological blockers of various Ca2+ entry pathways on intracellular Ca2+ accumulation, excitatory amino acid (EAA) release and neuronal death. Domoate produced a rapid and concentration-dependent increase in [Ca2+](i). the magnitude of which correlated closely with the severity of neuron loss. The increase in [Ca2+](i) was derived from activation of NMDA receptors, L-type voltage-sensitive calcium channels (VSCC) and the reversed mode of operation of the Na' /Ca2+ exchanger. When the level of neuroprotection conferred by pharmacological manipulation of these calcium entry pathways was regressed with the corresponding reductions in [Ca2+](i) load, it was observed that neuronal vulnerability is controlled preferentially by NMDA receptors. This observation is consistent with our previous study of brevetoxin-induced autocrine excitotoxicity and with the source specificity hypothesis of others [J. Neurochem. 71 (1998) 2349], which suggests that elevation of [Ca2+](i) in the vicinity of the NMDA receptor ion channel activates processes leading to neuronal death. (C) 2002 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:20 / 29
页数:10
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