Alcohol Regulates BK Surface Expression via Wnt/β-Catenin Signaling

It has been suggested that drug tolerance represents a form of learning and memory, but this has not been experimentally established at the molecular level. We show that a component of alcohol molecular tolerance (channel internalization) from rat hippocampal neurons requires protein synthesis, in common with other forms of learning and memory. We identify beta-catenin as a primary necessary protein. Alcohol increases beta-catenin, and blocking accumulation of beta-catenin blocks alcohol-induced internalization in these neurons. In transfected HEK293 cells, suppression of Wnt/beta-catenin signaling blocks ethanol-induced internalization. Conversely, activation of Wnt/beta catenin reduces BK current density. A point mutation in a putative glycogen synthase kinase phosophorylation site within the S10 region of BK blocks internalization, suggesting that Wnt/beta-catenin directly regulates alcohol-induced BK internalization via glycogen synthase kinase phosphorylation. These findings establish de novo protein synthesis and Wnt/beta-catenin signaling as critical in mediating a persistent form of BK molecular alcohol tolerance establishing a commonality with other forms of long-term plasticity.