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 language | English |
|---|---|
| Pages (from-to) | 133-139 |
| Number of pages | 7 |
| Journal | Toxicology Letters |
| Volume | 158 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 14 2005 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Toxicology
Cite this
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 journal › Article
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TY - JOUR
T1 - The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons
AU - LePage, K. T.
AU - Goeger, D.
AU - Yokokawa, F.
AU - Asano, T.
AU - Shioiri, T.
AU - Gerwick, W. H.
AU - Murray, Thomas F.
PY - 2005/8/14
Y1 - 2005/8/14
N2 - 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.
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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U2 - 10.1016/j.toxlet.2005.03.007
DO - 10.1016/j.toxlet.2005.03.007
M3 - Article
VL - 158
SP - 133
EP - 139
JO - Toxicology Letters
JF - Toxicology Letters
SN - 0378-4274
IS - 2
ER -