Small conductance, Ca(2+)-activated K(+) channels (SK channels) regulate neuronal excitability. We used patch clamp to study the actions of the neuroprotective drug riluzole on recombinant SK2 channels expressed in HEK293 cells and native SK channels underlying the afterhyperpolarization current (I(AHP)) in cultured hippocampal neurons. External riluzole activated whole-cell SK2 channel currents in HEK293 cells dialyzed with a Ca(2+)-free intracellular solution. When applied to the intracellular aspect of the membrane of giant inside-out patches, riluzole enhanced the membrane current activated by 100 nM Ca(2+) in a reversible and concentration-dependent manner; 30 microM riluzole applied to the intracellular aspect of the patches sensitized the channels to activation by Ca(2+), resulting in a leftward shift of the Ca(2+) activation curve. Riluzole also enhanced the I(AHP) and reduced the spontaneous action potential frequency in chemically stimulated neurons. Modulation of SK channel activity by riluzole may contribute to its cellular, behavioral, and clinical effects.