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Abstract
Alcohol abuse is a significant public health problem. Understanding the molecular effects of ethanol is important for the identification of at risk individuals, as well as the development of novel pharmacotherapies. The large conductance calcium sensitive potassium (BK) channel has emerged as an important player in the behavioral response to ethanol in genetic studies in several model organisms and in humans. The BK channel, slo-1, was identified in a forward genetics screen as a major ethanol target in C. elegans for the effects of ethanol on locomotion and egg-laying behaviors. Regulation of the expression of the BK channel, slo, in Drosophila underlies the development of rapid tolerance to ethanol and benzyl alcohol sedation. Rodent expression studies of the BK-encoding KCNMA1 gene have identified regulation of mRNA levels in response to ethanol exposure, and knock out studies in mice have demonstrated that the β subunits of the BK channel, β1 and β4, can modulate ethanol sensitivity of the channel in electrophysiological preparations, and can influence drinking behavior. In human genetics studies, both KCNMA1 and the genes encoding β subunits of the BK channel have been associated with alcohol dependence. This review describes the genetic data for a role for BK channels in mediating behavioral responses to ethanol across these species.
Highlights
Alcohol abuse is a significant worldwide socioeconomic problem, for which there are very few treatments
Genetic studies in C. elegans, Drosophila melanogaster, and mice have all demonstrated that BK channels are central to the behavioral effects of ethanol across these diverse phyla
It is interesting to note that while an important role for BK in ethanol response behaviors is apparently conserved, the actual behavioral outcomes of altering the function of BK channels are different across these models, which points to the complexity of the effects of ethanol on BK channels, and to the complexity of the roles of BK channels in ethanol response behaviors
Summary
Alcohol abuse is a significant worldwide socioeconomic problem, for which there are very few treatments. Reverse genetics allows for exquisite dissection of the function of particular genes in a phenotype of interest Model organisms, such as Caenorhabditis elegans and Drosophila melanogaster, provide powerful genetic tools, short generation times and relatively simple nervous systems with which to approach the problem of identifying the targets of a neuroactive drug and the physiological responses associated with the development of tolerance to such a drug (Schafer, 2004; Giacomotto and Ségalat, 2010; Devineni and Heberlein, 2013). Using forward and reverse genetics approaches, many different laboratories across several different model organisms and humans have identified the large conductance voltage and calcium-sensitive potassium (BK) channel as being important in modulating the behavioral effects of ethanol. The purpose of this review is to describe genetic evidence supporting a major role for BK as a central mediator of ethanol’s effects on behavior
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