Amino-termini Isoforms Of Slack K(Na) Channel Differentially Influence The Rate Of Neuronal Adaptation

The rates of activation and unitary properties of Na+-activated K+ currents, K(Na) currents have been found to vary substantially in different types of neurons. One class of K(Na) channels are encoded by the Slack gene. We have now determined that alternative RNA splicing gives rise to at least five different transcripts for Slack, one class of K channels which produce Slack channels that differ in their predicted cytoplasmic amino-termini and in their kinetic properties. Two of these, termed Slack-A channels, contain an amino-terminus domain closely resembling that of another class of K(Na) channels encoded by the Slick gene. Neuronal expression of Slack-A channels and of the previously described Slack isoform, now called Slack-B, are driven by independent promoters. Slack-A mRNAs were enriched in the brainstem and olfactory bulb and detected at significant levels in four different brain regions. Slack-A channels activate rapidly upon depolarization and, in single channel recordings in Xenopus oocytes, are characterized by multiple subconductance states with only brief transient openings to the fully open state. In contrast, Slack-B channels activate slowly over hundreds of milliseconds, with openings to the fully open state that are ∼6 fold longer than those for Slack-A channels. In numerical simulations, neurons in which outward currents are dominated by a Slack-A-like conductance adapt very rapidly to repeated or maintained stimulation over a wide range of stimulus strengths. In contrast, Slack-B currents promote rhythmic firing during maintained stimulation, and allow adaptation rate to vary with stimulus strength. Our data suggest that alternative promoters of the Slack gene differentially modulate the properties of neurons. Supported by NIH Grants NS61479 and DC01919.