The putative direct interaction of ethanol with the large-conductance Ca2+-activated K+ channel (BK channel) has spurred research on a molecular target that affects neurons and circuit function using both bottom-up and top-down approaches. Early studies showed that acute ethanol enhances BK channel function (Dopico et al., 2014). More recently, Bukiya et al. (2014) characterized an ethanol-sensing site in the channel-forming α subunit. Bottom-up studies have examined how changes in ethanol’s effects on BK channels alter behavior. For example, ethanol potentiates α and αβ4 BK channel open probability, but the potentiation of an α-only-containing BK channel shows rapid tolerance (Martin et al., 2008; Velázquez-Marrero et al., 2014), which could be related to behavioral tolerance (Treistman and Martin, 2009). Studies using genetic manipulation of BK channels have identified a role for these channels in ethanol-induced depressive behavior in C. elegans, tolerance in Drosophila, and several behavioral responses in rodents (reviewed in Bettinger and Davies, 2014). A top-down approach revealed molecular mechanisms responsible for these behavioral effects. Blocking BK channel transport to the presynaptic plasma membrane alters ethanol-induced locomotor depression in C. elegans
