BK channel clustering is required for normal behavioral alcohol sensitivity in C. elegans.

The large conductance, calcium- and voltage-activated potassium channel, known as the BK channel, is one of the central proteins that mediate alcohol intoxication and tolerance across species. Although ethanol targets BK channels through direct interaction, how ethanol-mediated BK channel activation causes behavioral intoxication is poorly understood. In. C. elegans, loss of function in SLO-1, the BK channel ortholog, confers profound ethanol resistance in movement and egg-laying behaviors. Here, we show that depletion of SLO-1 channels clustered at the active zones with no change in the overall channel expression level results in locomotory resistance to the intoxicating effect of ethanol, equivalent to that of slo-1 loss-of-function mutants. Likewise, depletion of clustered SLO-1 channels in the sarcolemma and neurons leads to ethanol-resistant egg-laying behavior. By contrast, reduction in the overall SLO-1 channel level by over 70% causes only moderate ethanol resistance in movement, and minimal, if any, resistance in egg laying. Our findings strongly suggest that behavioral ethanol sensitivity is conferred by local, but not global, depression of excitability via clustered BK channels. Given that clustered BK channels are functionally coupled to, and localize near, calcium channels, ethanol may mediate its behavioral effects by targeting BK channels and their coupled calcium channels.