Zonisamide (ZNS; 3-sulfamoylmethyl-1,2-benzisoxazole), as one of the newer antiepileptic drugs, has been demonstrated its broad-spectrum clinical efficacy on various neuropsychiatric disorders. However, little is known regarding the mechanism of ZNS actions on ion currents in neurons. We thus investigated its effect on ion currents in differentiated hippocampal 19-7 cells. In whole-cell configuration of patch-clamp technology, the ZNS (30 microM) reversibly increased the amplitude of K+ outward currents, and paxilline (1 microM) was effective in suppressing the ZNS-induced increase of K+ outward currents. In inside-out configuration, ZNS (30 microM) applied to the intracellular face of the membrane did not alter single-channel conductance; however, it did enhance the activity of large-conductance Ca2+-activated K+ (BK(Ca)) channels primarily by decreasing mean closed time. In addition, the EC50 value for ZNS-stimulated BK(Ca) channels was 34 microM. This drug caused a left shift in the activation curve of BK(Ca) channels, with no change in the gating charge of these channels. Moreover, ZNS at a concentration greater than 100 microM also reduced the amplitude of A-type K+ current in these cells. A simulation modeling based on hippocampal CA3 pyramidal neurons (Pinsky-Rinzel model) was also analyzed to investigate the inhibitory effect of ZNS on the firing of simulated action potentials. Taken together, this study suggests that, in hippocampal neurons during the exposure to ZNS, the ZNS-mediated effects on BK(Ca) channels and A-type K+ current could be potential mechanisms through which it affects neuronal excitability.