Although sodium-activated potassium channels (K Na ) have been suggested to shape various firing patterns in neurons, including action potential repolarization, their requirement for high concentrations of Na ϩ to gate conflicts with this view. We characterized K Na channels in adult rat dorsal root ganglion (DRG) neurons. Using immunohistochemistry, we found ubiquitous expression of the Slack K Na channel subunit in small-, medium-, and large-diameter DRG neurons. Basal K Na channel activity could be recorded from cell-attached patches of acutely dissociated neurons bathed in physiological saline, and yet in excised inside-out membrane patches, the Na ϩ EC 50 for K Na channels was typically high, ϳ50 mM. In some cases, however, K Na channel activity remained considerable after initial patch excision but decreased rapidly over time. Channel activity was restored in patches with high Na ϩ . The channel rundown after initial excision suggested that modulation of channels might be occurring through a diffusible cytoplasmic factor. Sequence analysis indicated that the Slack channel contains a putative nicotinamide adenine dinucleotide (NAD ϩ )-binding site; accordingly, we examined the modulation of native K Na and Slack channels by NAD ϩ . In inside-out-excised neuronal patch recordings, we found a decrease in the Na ϩ EC 50 for K Na channels from ϳ50 to ϳ20 mM when NAD ϩ was included in the perfusate. NAD ϩ also potentiated recombinant Slack channel activity. NAD ϩ modulation may allow K Na channels to operate under physiologically relevant levels of intracellular Na ϩ and hence provides an explanation as to how K Na channel can control normal neuronal excitability.