The Kv1.3 voltage-dependent potassium channel is expressed at high levels in mitral cells of the olfactory bulb (OB). Deletion of the Kv1.3 potassium channel gene (Kv1.3-/-) in mice lowers the threshold for detection of odors, increases the ability to discriminate between odors, and alters the firing pattern of mitral cells. We have now found that loss of Kv1.3 produces a compensatory increase in Na(+)-activated K(+) currents (K(Na)) in mitral cells. Levels of the K(Na) channel subunit Slack-B determined by Western blotting are substantially increased in the OB from Kv1.3-/- animals compared with those of wildtype animals. In voltage-clamp recordings of OB slices, elevation of intracellular sodium from 0 to 60 mM increased mean outward currents by 15% in mitral cells from wildtype animals and by 40% in cells from Kv1.3-/- animals. In Kv1.3-/- cells, K(Na) current could even be detected with 0 mM Na(+) internal solutions, provided extracellular Na(+) was present, and this current could be abolished by TTX and ZD7288, blockers of Na(+) influx through voltage-dependent Na(+) channels and H-channels, respectively. The role of enhanced expression of Slack subunits in the increase of K(Na) current in Kv1.3-/- cells was also confirmed using an RNA interference (RNA(i)) approach to suppress Slack expression in primary cultures of olfactory neurons. In Kv1.3-/- neurons, treatment with Slack-specific RNA(i) inhibited approximately 75% of the net outward current, whereas in wildtype cells, the same treatment suppressed only about 25% of the total current. Scrambled and mismatched RNA(i) oligonucleotides failed to suppress currents. Our findings raise the possibility that the olfactory phenotype of Kv1.3-/- animals results in part from an enhancement of K(Na) currents.