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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

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Huang C. W., Tsai J. J., Huang C. C., Wu S. N.

Journal of Physiology and Pharmacology

2009

tom 60

nr 4

37-47

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 IC50 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.

Ograniczanie wyników

1 Journal of Physiology and Pharmacology

1 Huang C. C.

1 Huang C. W.

1 Tsai J. J.

1 Wu S. N.

1 2009

Wyniki wyszukiwania

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