| 16039402 |
LePage KT, Goeger D, Yokokawa F, Asano T, Shioiri T, Gerwick WH, Murray TF: The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons. Toxicol Lett. 2005 Aug 14;158(2):133-9. Epub 2005 Apr 9.
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 microM) 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 [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 [3H] batrachotoxin ([3H] BTX) to neurotoxin site 2 on the TTX-VSSC. Although kalkitoxin was without effect on the basal binding of [3H] BTX to intact cerebellar granule neurons, in the presence of the positive allosteric modulator, deltamethrin, [3H] BTX binding was inhibited by KTx-7 in a concentration-dependent manner (11.9 nM [IC50=3.8-37.2 nM, 95% CI]). These results provide both direct and functional evidence for an interaction of kalkitoxin with the neuronal TTX-VSSC. |
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