Activation by zonisamide, a newer antiepileptic drug, of large-conductance calcium-activated potassium channel in differentiated hippocampal neuron-derived H19-7 cells

Chin Wei Huang, Chao Ching Huang, Sheng Nan Wu

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22 Citations (Scopus)

Abstract

Zonisamide (ZNS; 3-sulfamoylmethyl-1,2-benzisoxazole), as one of the newer antiepileptic drugs, has been demonstrated its broad-spectrum clinical efficacy on various neuropsychiatric disorders. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. In whole-cell configuration of patch-clamp technology, the ZNS (30 μM) reversibly increased the amplitude of K+ outward currents, and paxilline (1 μM) was effective in suppressing the ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 μM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+- activated K+ (BKCa) channels primarily by decreasing mean closed time. In addition, the EC50 value for ZNS-stimulated BK Ca channels was 34 μM. This drug caused a left shift in the activation curve of BKCa channels, with no change in the gating charge of these channels. Moreover, ZNS at a concentration greater than 100 μM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that, in hippocampal neurons during the exposure to ZNS, the ZNS-mediated effects on BKCa channels and A-type K+ current could be potential mechanisms through which it affects neuronal excitability.

Original languageEnglish
Pages (from-to)98-106
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume321
Issue number1
DOIs
Publication statusPublished - Apr 2007
Externally publishedYes

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zonisamide
Large-Conductance Calcium-Activated Potassium Channels
Anticonvulsants
Neurons
Ions
Calcium-Activated Potassium Channels
Intracellular Membranes
Pyramidal Cells
Action Potentials
Technology
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Activation by zonisamide, a newer antiepileptic drug, of large-conductance calcium-activated potassium channel in differentiated hippocampal neuron-derived H19-7 cells",
abstract = "Zonisamide (ZNS; 3-sulfamoylmethyl-1,2-benzisoxazole), as one of the newer antiepileptic drugs, has been demonstrated its broad-spectrum clinical efficacy on various neuropsychiatric disorders. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. In whole-cell configuration of patch-clamp technology, the ZNS (30 μM) reversibly increased the amplitude of K+ outward currents, and paxilline (1 μM) was effective in suppressing the ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 μM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+- activated K+ (BKCa) channels primarily by decreasing mean closed time. In addition, the EC50 value for ZNS-stimulated BK Ca channels was 34 μM. This drug caused a left shift in the activation curve of BKCa channels, with no change in the gating charge of these channels. Moreover, ZNS at a concentration greater than 100 μM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that, in hippocampal neurons during the exposure to ZNS, the ZNS-mediated effects on BKCa channels and A-type K+ current could be potential mechanisms through which it affects neuronal excitability.",
author = "Huang, {Chin Wei} and Huang, {Chao Ching} and Wu, {Sheng Nan}",
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T1 - Activation by zonisamide, a newer antiepileptic drug, of large-conductance calcium-activated potassium channel in differentiated hippocampal neuron-derived H19-7 cells

AU - Huang, Chin Wei

AU - Huang, Chao Ching

AU - Wu, Sheng Nan

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N2 - Zonisamide (ZNS; 3-sulfamoylmethyl-1,2-benzisoxazole), as one of the newer antiepileptic drugs, has been demonstrated its broad-spectrum clinical efficacy on various neuropsychiatric disorders. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. In whole-cell configuration of patch-clamp technology, the ZNS (30 μM) reversibly increased the amplitude of K+ outward currents, and paxilline (1 μM) was effective in suppressing the ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 μM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+- activated K+ (BKCa) channels primarily by decreasing mean closed time. In addition, the EC50 value for ZNS-stimulated BK Ca channels was 34 μM. This drug caused a left shift in the activation curve of BKCa channels, with no change in the gating charge of these channels. Moreover, ZNS at a concentration greater than 100 μM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that, in hippocampal neurons during the exposure to ZNS, the ZNS-mediated effects on BKCa channels and A-type K+ current could be potential mechanisms through which it affects neuronal excitability.

AB - Zonisamide (ZNS; 3-sulfamoylmethyl-1,2-benzisoxazole), as one of the newer antiepileptic drugs, has been demonstrated its broad-spectrum clinical efficacy on various neuropsychiatric disorders. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. In whole-cell configuration of patch-clamp technology, the ZNS (30 μM) reversibly increased the amplitude of K+ outward currents, and paxilline (1 μM) was effective in suppressing the ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 μM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+- activated K+ (BKCa) channels primarily by decreasing mean closed time. In addition, the EC50 value for ZNS-stimulated BK Ca channels was 34 μM. This drug caused a left shift in the activation curve of BKCa channels, with no change in the gating charge of these channels. Moreover, ZNS at a concentration greater than 100 μM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that, in hippocampal neurons during the exposure to ZNS, the ZNS-mediated effects on BKCa channels and A-type K+ current could be potential mechanisms through which it affects neuronal excitability.

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