Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-Kα and pandinustoxin-Kα

K. N. Juhng, T. G. Kokate, S. Yamaguchi, B. Y. Kim, R. S. Rogowski, M. P. Blaustein, Michael A Rogawski

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The scorpion venom peptide toxins tityustoxin-Kα (TsTx-Kα) and pandinustoxin-Kα (PiTx-Kα) are novel, highly potent and selective blockers of voltage-activated K + channels. PiTx-Kα preferentially blocks rapidly inactivating (A-type) K+ channels whereas TsTx-Kα is selective for slowly inactivating (delayed rectifier-type) channels. K+ channel blockers are known to induce seizures, but the specific K+ channel types that can serve as convulsant targets are not well defined. To address this issue, we examined for convulsant activity the K+ channel type-specific scorpion toxins and the selective K+ channel antagonists 4-aminopyridine (4-AP), an inhibitor of A-type voltage-activated K+ channels, and paxilline, a selective blocker of large conductance (maxi K) Ca2+-activated K+ channels. Intracerebroventricular injection of recombinant TsTx-Kα and PiTx- Kα in mice produced limbic and clonic-tonic seizures. The severity of the seizures increased during the 60-min period following injection, culminating in continuous clonic seizure activity (status epilepticus), tonic hindlimb extension, and eventually in death. The estimated doses producing limbic and clonic seizures in 50% of animals (CD50) for TsTx-Kα and PiTx-Kα were 9 and 33 ng, respectively. 4-AP produced seizure activity similar to the toxins (CD50, 76 ng) whereas paxilline failed to induce seizures at doses up to 13.5 μg. Carbamazepine protected fully against the toxin- and 4-AP-induced seizures whereas phenytoin had variable activity against the clonic component although it was protective against tonic hindlimb extension. The AMPA receptor antagonist GYKI 52466 also conferred full protection against toxin- induced seizures, but the NMDA receptor antagonists (R)-CPP and dizocilpine failed to affect limbic and clonic seizures, although they protected against hindlimb extension. We conclude that selective blockade of delayed rectifier- or A-type voltage-activated K+ channels can produce limbic, clonic and tonic seizures, whereas blockade of maxi K-type Ca2+-activated K+ channels does not. The convulsant effects may be related to enhanced glutamate release and, in the case of the limbic and clonic convulsions, activation of AMPA receptors.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalEpilepsy Research
Volume34
Issue number2-3
DOIs
StatePublished - Apr 1 1999
Externally publishedYes

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Scorpion Venoms
Seizures
Peptides
Convulsants
4-Aminopyridine
Hindlimb
Calcium-Activated Potassium Channels
AMPA Receptors
tityustoxin
Scorpions
Injections
Dizocilpine Maleate
Status Epilepticus
Carbamazepine
Phenytoin
N-Methyl-D-Aspartate Receptors
Glutamic Acid

Keywords

  • 4-aminopyridine
  • AMPA receptor antagonist
  • K channel blocker
  • Pandinustoxin-Kα
  • Paxilline
  • Tityustoxin-Kα

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Neurology

Cite this

Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-Kα and pandinustoxin-Kα. / Juhng, K. N.; Kokate, T. G.; Yamaguchi, S.; Kim, B. Y.; Rogowski, R. S.; Blaustein, M. P.; Rogawski, Michael A.

In: Epilepsy Research, Vol. 34, No. 2-3, 01.04.1999, p. 177-186.

Research output: Contribution to journalArticle

Juhng, K. N. ; Kokate, T. G. ; Yamaguchi, S. ; Kim, B. Y. ; Rogowski, R. S. ; Blaustein, M. P. ; Rogawski, Michael A. / Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-Kα and pandinustoxin-Kα. In: Epilepsy Research. 1999 ; Vol. 34, No. 2-3. pp. 177-186.
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abstract = "The scorpion venom peptide toxins tityustoxin-Kα (TsTx-Kα) and pandinustoxin-Kα (PiTx-Kα) are novel, highly potent and selective blockers of voltage-activated K + channels. PiTx-Kα preferentially blocks rapidly inactivating (A-type) K+ channels whereas TsTx-Kα is selective for slowly inactivating (delayed rectifier-type) channels. K+ channel blockers are known to induce seizures, but the specific K+ channel types that can serve as convulsant targets are not well defined. To address this issue, we examined for convulsant activity the K+ channel type-specific scorpion toxins and the selective K+ channel antagonists 4-aminopyridine (4-AP), an inhibitor of A-type voltage-activated K+ channels, and paxilline, a selective blocker of large conductance (maxi K) Ca2+-activated K+ channels. Intracerebroventricular injection of recombinant TsTx-Kα and PiTx- Kα in mice produced limbic and clonic-tonic seizures. The severity of the seizures increased during the 60-min period following injection, culminating in continuous clonic seizure activity (status epilepticus), tonic hindlimb extension, and eventually in death. The estimated doses producing limbic and clonic seizures in 50{\%} of animals (CD50) for TsTx-Kα and PiTx-Kα were 9 and 33 ng, respectively. 4-AP produced seizure activity similar to the toxins (CD50, 76 ng) whereas paxilline failed to induce seizures at doses up to 13.5 μg. Carbamazepine protected fully against the toxin- and 4-AP-induced seizures whereas phenytoin had variable activity against the clonic component although it was protective against tonic hindlimb extension. The AMPA receptor antagonist GYKI 52466 also conferred full protection against toxin- induced seizures, but the NMDA receptor antagonists (R)-CPP and dizocilpine failed to affect limbic and clonic seizures, although they protected against hindlimb extension. We conclude that selective blockade of delayed rectifier- or A-type voltage-activated K+ channels can produce limbic, clonic and tonic seizures, whereas blockade of maxi K-type Ca2+-activated K+ channels does not. The convulsant effects may be related to enhanced glutamate release and, in the case of the limbic and clonic convulsions, activation of AMPA receptors.",
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T1 - Induction of seizures by the potent K+ channel-blocking scorpion venom peptide toxins tityustoxin-Kα and pandinustoxin-Kα

AU - Juhng, K. N.

AU - Kokate, T. G.

AU - Yamaguchi, S.

AU - Kim, B. Y.

AU - Rogowski, R. S.

AU - Blaustein, M. P.

AU - Rogawski, Michael A

PY - 1999/4/1

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N2 - The scorpion venom peptide toxins tityustoxin-Kα (TsTx-Kα) and pandinustoxin-Kα (PiTx-Kα) are novel, highly potent and selective blockers of voltage-activated K + channels. PiTx-Kα preferentially blocks rapidly inactivating (A-type) K+ channels whereas TsTx-Kα is selective for slowly inactivating (delayed rectifier-type) channels. K+ channel blockers are known to induce seizures, but the specific K+ channel types that can serve as convulsant targets are not well defined. To address this issue, we examined for convulsant activity the K+ channel type-specific scorpion toxins and the selective K+ channel antagonists 4-aminopyridine (4-AP), an inhibitor of A-type voltage-activated K+ channels, and paxilline, a selective blocker of large conductance (maxi K) Ca2+-activated K+ channels. Intracerebroventricular injection of recombinant TsTx-Kα and PiTx- Kα in mice produced limbic and clonic-tonic seizures. The severity of the seizures increased during the 60-min period following injection, culminating in continuous clonic seizure activity (status epilepticus), tonic hindlimb extension, and eventually in death. The estimated doses producing limbic and clonic seizures in 50% of animals (CD50) for TsTx-Kα and PiTx-Kα were 9 and 33 ng, respectively. 4-AP produced seizure activity similar to the toxins (CD50, 76 ng) whereas paxilline failed to induce seizures at doses up to 13.5 μg. Carbamazepine protected fully against the toxin- and 4-AP-induced seizures whereas phenytoin had variable activity against the clonic component although it was protective against tonic hindlimb extension. The AMPA receptor antagonist GYKI 52466 also conferred full protection against toxin- induced seizures, but the NMDA receptor antagonists (R)-CPP and dizocilpine failed to affect limbic and clonic seizures, although they protected against hindlimb extension. We conclude that selective blockade of delayed rectifier- or A-type voltage-activated K+ channels can produce limbic, clonic and tonic seizures, whereas blockade of maxi K-type Ca2+-activated K+ channels does not. The convulsant effects may be related to enhanced glutamate release and, in the case of the limbic and clonic convulsions, activation of AMPA receptors.

AB - The scorpion venom peptide toxins tityustoxin-Kα (TsTx-Kα) and pandinustoxin-Kα (PiTx-Kα) are novel, highly potent and selective blockers of voltage-activated K + channels. PiTx-Kα preferentially blocks rapidly inactivating (A-type) K+ channels whereas TsTx-Kα is selective for slowly inactivating (delayed rectifier-type) channels. K+ channel blockers are known to induce seizures, but the specific K+ channel types that can serve as convulsant targets are not well defined. To address this issue, we examined for convulsant activity the K+ channel type-specific scorpion toxins and the selective K+ channel antagonists 4-aminopyridine (4-AP), an inhibitor of A-type voltage-activated K+ channels, and paxilline, a selective blocker of large conductance (maxi K) Ca2+-activated K+ channels. Intracerebroventricular injection of recombinant TsTx-Kα and PiTx- Kα in mice produced limbic and clonic-tonic seizures. The severity of the seizures increased during the 60-min period following injection, culminating in continuous clonic seizure activity (status epilepticus), tonic hindlimb extension, and eventually in death. The estimated doses producing limbic and clonic seizures in 50% of animals (CD50) for TsTx-Kα and PiTx-Kα were 9 and 33 ng, respectively. 4-AP produced seizure activity similar to the toxins (CD50, 76 ng) whereas paxilline failed to induce seizures at doses up to 13.5 μg. Carbamazepine protected fully against the toxin- and 4-AP-induced seizures whereas phenytoin had variable activity against the clonic component although it was protective against tonic hindlimb extension. The AMPA receptor antagonist GYKI 52466 also conferred full protection against toxin- induced seizures, but the NMDA receptor antagonists (R)-CPP and dizocilpine failed to affect limbic and clonic seizures, although they protected against hindlimb extension. We conclude that selective blockade of delayed rectifier- or A-type voltage-activated K+ channels can produce limbic, clonic and tonic seizures, whereas blockade of maxi K-type Ca2+-activated K+ channels does not. The convulsant effects may be related to enhanced glutamate release and, in the case of the limbic and clonic convulsions, activation of AMPA receptors.

KW - 4-aminopyridine

KW - AMPA receptor antagonist

KW - K channel blocker

KW - Pandinustoxin-Kα

KW - Paxilline

KW - Tityustoxin-Kα

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