GIRK2 channels in liposomes, controlling the components of the bilayer, and adding alcohol in isolation of any other proteins, we could overcome these previous limitations and demonstrate that intoxicating concentrations of ethanol, i.e., >20 mM, directly activate GIRK2 channels in the presence of PIP2. For reference, a blood alcohol level of 0.08% is ~ 17 mM, binge-drinking levels can reach 50 mM, and the anesthetic concentration is around 190 mM52. On the other hand, we find that two types of lipid disruptive amphiphiles, e.g., β-octyl glucoside (β-OG) and capsaicin, do not activate GIRK2 channels. Thus, the mechanism of ethanol activation of GIRK2 channels is unlikely to involve an indirect component from an alcohol-dependent changes in the membrane lipids or from Gβγ subunits.
