Journal
TOXICOLOGY LETTERS
Volume 158, Issue 2, Pages 133-139Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2005.03.007
Keywords
neurotoxicity; sodium channel; neuron; Ca2+
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Funding
- NIGMS NIH HHS [GM 63554] Funding Source: Medline
- NINDS NIH HHS [R01 NS053398] Funding Source: Medline
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The marine neurotoxin kalkitoxin, a thiazoline-containing lipid derived from the pantropical marine cyanobacterium Lyngbya majuscula, was assayed for interaction with the tetrodotoxin-sensitive, voltage-sensitive sodium channel (TTX-VSSC) in cerebellar granule neuron cultures (CGN). The naturally occurring isomer of kalkitoxin (KTx-7) blocked veratridine-induced (30 mu M) neurotoxicity in a concentration-dependent manner (EC50 22.7 nM [9.5-53.9 nM, 95% confidence interval {CI}]))in CGN. Kalkitoxin was a potent inhibitor (EC50 26.1 nM L 12.3-55.0 nM, 95% CI]) of the elevation of intracellular Ca2+ concentration [Ca2+](i) that accompanies exposure of CGN to veratridine. To further explore the potential interaction of KTx-7 with TTX-VSSC, we assessed the influence of KTX-7 on the binding of [H-3]batrachotoxin ([H-3]BTX) to neurotoxin site 2 on the TTX-VSSC. Although kalkitoxin was without effect on the basal binding of [H-3]BTX to intact crebellar granule neurons, in the presence of the positive allosteric modulator, deltamethrin, [H-3]BTX binding was inhibited by KTx-7 in a concentration-dependent manner (11.9 nM [IC50 = 3.8-37.2 nM, 95% Cl]). These results provide both direct and functional evidence for an interaction of kalkitoxin with the neuronal TTX-VSSC. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
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