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

Abstract

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 ␤-catenin as a primary necessary protein.Alcohol increases ␤-catenin, and blocking accumulation of ␤-catenin blocks alcohol-induced internalization in these neurons. In transfected HEK293 cells, suppression of Wnt/␤-catenin signaling blocks ethanol-induced internalization. Conversely, activation of Wnt/␤-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/␤-catenin directly regulates alcohol-induced BK internalization via glycogen synthase kinase phosphorylation. These findings establish de novo protein synthesis and Wnt/␤-catenin signaling as critical in mediating a persistent form of BK molecular alcohol tolerance establishing a commonality with other forms of long-term plasticity.

Transcriptomic changes due to early, chronic intermittent alcohol exposure during forebrain development implicate WNT signaling, cell‐type specification, and cortical regionalization as primary determinants of fetal alcohol syndrome

“…While the effect of EtOH on transcriptional regulation in development may be direct through restructuring of the chromatin landscape (Mews et al, 2019), other studies suggest that the majority of alterations are likely via changes to transcript and protein levels that lie relatively upstream in regulatory cascades (Ehrhart et al, 2019). Indeed, many transcripts related to WNT signaling were found to be altered in these data, consistent with previous reports (Vangipuram & Lyman, 2012; Velázquez‐Marrero et al, 2016; Zhu et al, 2017). Based on the role of WNT signaling in regulating areal identity (Harrison‐Uy & Pleasure, 2012 and Mulligan & Cheyette, 2012), we examined the alcohol‐associated dysregulation of genes with regionally restricted patterns of expression and found evidence for altered A‐P/D‐V specification.…”

Glial gene networks associated with alcohol dependence

“…4B). Notch- and Wnt- related genes have been previously shown to be altered by chronic alcohol exposure 15,66 and to regulate alcohol-induced synaptic remodeling 67 . Recent studies suggest they may be important for controlling mature astrocyte function and plasticity 68,69 .…”

Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence

“…We posit that the tightly coordinated ethanol regulation of gene expression in this Gsk3b-related network suggests an important role in neuroadaptation to ethanol and that some portion of the risk for alcohol dependence conferred by variants in individual genes and the network as a whole may be due to differences in individuals' initial ethanol response, given that low level of response is a known predictor of future alcoholism [33]. In general support of this concept, two recent reports suggest GSK3B is a potential modulator of chronic ethanol adaptations in signaling systems involving Kcnma1 [58] and dopamine D2 receptors [59]. Just because Gsk3b was a highly-interconnected gene in our BXD study, this does not necessarily imply that ethanol-responsive genes correlated with Gsk3b are regulated by Gsk3b itself.…”