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

Purpose: We investigated the effects of lamotrigine (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 μM-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 μM. 4-Aminopyridine (1 mM), quinidine (30 μM), and capsaicin (30 μM) were effective in suppressing the amplitude of I_A, whereas tetraethylammonium chloride (1 mM) and gabapentin (100 μM) had no effect on it. The time course for the inactivation of I_A was changed to the biexponential process during cell exposure to LTG (100 μM). LTG (300 μM) 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 μM) 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.