The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons

K. T. LePage, D. Goeger, F. Yokokawa, T. Asano, T. Shioiri, W. H. Gerwick, Thomas F. Murray

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Abstract

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 μM) 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 crebellar 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.

Original languageEnglish
Pages (from-to)133-139
Number of pages7
JournalToxicology Letters
Volume158
Issue number2
DOIs
StatePublished - Aug 14 2005
Externally publishedYes

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Lipopeptides
Sodium Channels
Neurons
Tetrodotoxin
Veratridine
Electric potential
Neurotoxins
Confidence Intervals
Batrachotoxins
Cyanobacteria
Isomers
Modulators
Inhibitory Concentration 50
kalkitoxin
Lipids

All Science Journal Classification (ASJC) codes

  • Toxicology

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The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons. / LePage, K. T.; Goeger, D.; Yokokawa, F.; Asano, T.; Shioiri, T.; Gerwick, W. H.; Murray, Thomas F.

In: Toxicology Letters, Vol. 158, No. 2, 14.08.2005, p. 133-139.

Research output: Contribution to journalArticle

LePage, K. T. ; Goeger, D. ; Yokokawa, F. ; Asano, T. ; Shioiri, T. ; Gerwick, W. H. ; Murray, Thomas F. / The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons. In: Toxicology Letters. 2005 ; Vol. 158, No. 2. pp. 133-139.
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abstract = "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 μM) 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 crebellar 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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AU - Yokokawa, F.

AU - Asano, T.

AU - Shioiri, T.

AU - Gerwick, W. H.

AU - Murray, Thomas F.

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AB - 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 μM) 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 crebellar 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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