Theories of molecular mechanisms of action of alcohol in the central nervous system have evolved from an earlier ‘lipid hypothesis’, in which actions of ethanol on neuronal membranes was explained mainly in terms of actions on membrane lipids, secondarily affecting proteins, to the recent ‘protein hypothesis’, which is predicated on findings (driven by molecular mutagenesis studies) that alcohol can interact directly with membrane proteins to affect function [39,43,44]. Indeed, this change in thinking represents a major paradigm shift. Moreover, our understanding of the relationship between BK molecular structure and ethanol interaction has become increasingly sophisticated [4,45]. However, it might be wrong to replace our focus on lipids as sole targets with a new view in which proteins are the sole targets. In fact, our understanding of the lipid environment at the level of nanoscale domains has advanced significantly and reveals the importance of this heterogeneous group of organic compounds [46]. We believe that the most reasonable interpretation is that although the drug interacts directly with proteins, the lipid environment modulates this interaction or the effects of this interaction.
