Inhibitory effect of lamotrigine on A-type potassium current in hippocampal neuron-derived H19-7 cells

Purpose: We investigated the effects of lamotrigme (LTG) on the rapidly inactivating A-type K+ current (I-A) in embryonal hippocampal neurons. Methods: The whole-cell configuration of the patch-clamp technique was applied to investigate the ion currents in cultured hippocampal neuron-derived H19-7 cells in the presence of LTG. Effects of various related compounds on I-A in H19-7 cells were compared. Results: LTG (30 muM-3 mM) caused a reversible reduction in the amplitude of I-A. The median inhibitory concentration (IC50) value required for the inhibition Of I-A by LTG was 160 muM. 4-Aminopyridine (1 mM), quinidine (30 muM), and capsaicin (30 muM) were effective in suppressing the amplitude Of I-A, whereas tetraethylammonium chloride (1 mM) and gabapentin (100 muM) had no effect on it. The time course for the inactivation Of I-A was changed to the biexponential process during cell expo-sure to LTG (100 muM). LTG (300 muM) could shift the steady-state inactivation Of I-A to a more negative membrane potential by approximately -10 mV, although it had no effect on the slope of the inactivation curve. Moreover, LTG (100 muM) produced a significant prolongation in the recovery Of I-A inactivation. Therefore in addition to the inhibition of voltage-dependent Na+ channels, LTG could interact with the A-type K+ channels to suppress the amplitude Of I-A. The blockade of I-A by LTG does not simply reduce current magnitude, but alters Current kinetics, suggesting a state-dependent blockade. LTG might have a higher affinity to the inactivated state than to the resting state of the I-A channel. Conclusions: This study suggests that in hippocampal neurons, during exposure to LTG, the LTG-mediated inhibition of these K+ channels could be one of the ionic mechanisms underlying the increased neuronal excitability.