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- Title
Brevetoxin-Induced Autocrine Excitotoxicity Is Associated with ManifoldRoutes of Ca[sup 2+] Influx.
- Authors
Berman, Frederick W.; Murray, Thomas F.
- Abstract
Abstract: Real-time alterations in intracellular Ca[sup 2+] ([Ca[sup 2+]][sub i]) were monitored in fluo-3-loaded cerebellar granule neurons (CGNs) exposed to the brevetoxin PbTx-1. [Ca[sup 2+]][sub i] was measured using a fluorescent plate reader (FLIPR), which measures simultaneously the mean intracellular Ca[sup 2+] change in a population of cultured cells in each well of a 96-well plate. PbTx-1 produced rapid and concentration-dependent increases in neuronal [Ca[sup 2+]][sub i] with a potency nearly identical to that determined previously for PbTx-1-induced neurotoxicity. The NMDA receptor antagonists MK-801, dextrorphan, and D(-)-2-amino-5-phosphonopentanoic acid, and tetanus toxin, an inhibitor of Ca[sup 2+]-dependent exocytotic neurotransmitter release, effected significant reductions in both the integrated fluo-3 fluorescence response and excitatory amino acid release and protected CGNs against PbTx-1 neurotoxicity. The L-type Ca[sup 2+] channel antagonist nifedipine produced a modest reduction in the fluo-3 response but reduced substantially the plateau phase of the PbTx-1 increment in [Ca[sup 2+]][sub i] when combined with MK-801. When nifedipine and MK-801 were combined with the Na[sup +]/Ca[sup 2+] exchanger (reversed mode) inhibitor KB-R7943, the PbTx-1 increment in [Ca[sup 2+]][sub i] was nearly completely attenuated. These data show that Ca[sup 2+] entry into PbTx-1-exposed CGNs occurs through three primary routes: NMDA receptor ion channels, L-type Ca[sup 2+] channels, and reversal of the Na[sup +]/Ca[sup 2+] exchanger. There was a close correlation between reduction of the integrated fluo-3 fluorescence response and the level of neuroprotection afforded by blockers of each Ca[sup 2+] entry pathway; however, simultaneous blockade of L-type Ca[sup 2+] channels and the Na[sup +]/Ca[sup 2+]...
- Subjects
AUTOCRINE mechanisms; CALCIUM; NEUROTOXICOLOGY
- Publication
Journal of Neurochemistry, 2000, Vol 74, Issue 4, p1443
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1046/j.1471-4159.2000.0741443.x