We will describe three separate approaches describing the response and adaptation of BK to alcohol, first exploring molecular tolerance from a very reductionist level, then through analysis in increasingly complex situations, before finally addressing the role of BK channel auxiliary proteins in tolerance and the modulation of drinking behavior in mice. Importantly, the effects of alcohol on human BK channels transfected into cell lines are remarkably similar to the response of BK channels in rodent neurons [42], suggesting that the findings described in this review will be applicable to the human condition. It should be noted that the first approach to be described represents a potential role of lipids in alcohol drinking and tolerance. Hopefully, future research will address the changes in membrane lipids that occur during drinking and also the consequences of these changes for dependence and addiction. The second approach (epigenetic studies) provides a potent mechanism for tolerance but awaits evidence linking it to altered drinking behavior. The last approach, describing the influence for the BK β4 subunit on acute tolerance, shows both the effect at the molecular and cellular levels and the consequences for drinking behavior in mice.
