NAD ⁺ activates K _Na channels in dorsal root ganglion neurons

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 ⁺ 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 ⁺ EC ₅₀ for K _Na channels was typically high, ~50 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 ⁺. 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 ⁺)-binding site; accordingly, we examined the modulation of native K _Na and Slack channels by NAD. In inside-out-excised neuronal patch recordings, we found a decrease in the Na EC ₅₀ for K _Na channels from ~50 to ~20 mm when NAD ⁺ was included in the perfusate. NAD ⁺ also potentiated recombinant Slack channel activity. NAD ⁺ modulation may allow K _Na channels to operate under physiologically relevant levels of intracellular Na ⁺ and hence provides an explanation as to how K _Na channel can control normal neuronal excitability.