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

Frederick W. Berman, Keith T. LePage, Thomas F. Murray

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63 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20-29
Number of pages10
JournalBrain Research
Volume924
Issue number1
DOIs
StatePublished - Jan 4 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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