Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (Kv3.1)

Contribution to the firing of action potentials

C. W. Huang, J. J. Tsai, C. C. Huang, Sheng Nan Wu

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the KV3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K+ current (IK(DR)) in a concentration-dependent manner with an IC 50 value of 37 μM. LEV (30 μM) shifted the steady-state activation of IK(DR) to a more positive potential by 10 mV, without shifting the steady-state inactivation of IK(DR). Neither Na +, nor erg (ether-a-go-go-related)-mediated K+ and ATP-sensitive K+ currents were affected by LEV (100 μM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating IK(DR) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating IK(DR) (KV3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.

Original languageEnglish
Pages (from-to)37-47
Number of pages11
JournalJournal of Physiology and Pharmacology
Volume60
Issue number4
Publication statusPublished - Dec 2009
Externally publishedYes

Fingerprint

etiracetam
Action Potentials
Potassium
Pyrrolidinones
Neurons
Generalized Epilepsy
Bucladesine
Partial Epilepsy
Ether
Membrane Potentials
Anticonvulsants

Keywords

  • Action potential
  • Delayed rectifier K current
  • Differentiated NG108-15 cell
  • Levetiracetam
  • Na current
  • Simulation

ASJC Scopus subject areas

  • Pharmacology
  • Physiology

Cite this

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title = "Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (Kv3.1): Contribution to the firing of action potentials",
abstract = "Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the KV3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K+ current (IK(DR)) in a concentration-dependent manner with an IC 50 value of 37 μM. LEV (30 μM) shifted the steady-state activation of IK(DR) to a more positive potential by 10 mV, without shifting the steady-state inactivation of IK(DR). Neither Na +, nor erg (ether-a-go-go-related)-mediated K+ and ATP-sensitive K+ currents were affected by LEV (100 μM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating IK(DR) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating IK(DR) (KV3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.",
keywords = "Action potential, Delayed rectifier K current, Differentiated NG108-15 cell, Levetiracetam, Na current, Simulation",
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T2 - Contribution to the firing of action potentials

AU - Huang, C. W.

AU - Tsai, J. J.

AU - Huang, C. C.

AU - Wu, Sheng Nan

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N2 - Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the KV3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K+ current (IK(DR)) in a concentration-dependent manner with an IC 50 value of 37 μM. LEV (30 μM) shifted the steady-state activation of IK(DR) to a more positive potential by 10 mV, without shifting the steady-state inactivation of IK(DR). Neither Na +, nor erg (ether-a-go-go-related)-mediated K+ and ATP-sensitive K+ currents were affected by LEV (100 μM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating IK(DR) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating IK(DR) (KV3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.

AB - Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the KV3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K+ current (IK(DR)) in a concentration-dependent manner with an IC 50 value of 37 μM. LEV (30 μM) shifted the steady-state activation of IK(DR) to a more positive potential by 10 mV, without shifting the steady-state inactivation of IK(DR). Neither Na +, nor erg (ether-a-go-go-related)-mediated K+ and ATP-sensitive K+ currents were affected by LEV (100 μM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating IK(DR) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating IK(DR) (KV3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.

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