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.
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 K(V)3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K(+) current (I(K(DR))) in a concentration-dependent manner with an IC(50) value of 37 microM. LEV (30 microM) shifted the steady-state activation of I(K(DR)) to a more positive potential by 10 mV, without shifting the steady-state inactivation of I(K(DR)). Neither Na(+), nor erg (ether-a-go-go-related)-mediated K(+) and ATP-sensitive K(+) currents were affected by LEV (100 microM). 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 I(K(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 I(K(DR)) (K(V)3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.
Huang
C W
CW
Department of Neurology, National Cheng Kung University School of Medicine, Tainan, Taiwan.
Tsai
J J
JJ
Huang
C C
CC
Wu
S N
SN
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000187:drug effects; D003198:Computer Simulation; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D005786:Gene Expression Regulation; D015640:Ion Channel Gating / Q000187:drug effects*; D054086:KATP Channels; D000077287:Levetiracetam; D009431:Neural Conduction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051670:Shaw Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels
D000927:Anticonvulsants; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; D054086:KATP Channels; D051670:Shaw Potassium Channels; D015222:Sodium Channels; D000077287:Levetiracetam; D010889:Piracetam