Interestingly, whereas 1-octanol inhibits GIRK channels, co-application of 1-octanol with EtOH has no effect on EtOH-mediated activation, also raising the possibility of a second site for inhibition7. The net effect of alcohol modulation in GIRK channels would therefore be determined by the relative potencies of activation and inhibition. In support of this, we found that bath application of 1-PeOH inhibited GIRK2 channels but induced a large current immediately after washout (Supplementary Fig. S1), revealing two components of alcohol modulation. It is notable that MPD predominantly activates GIRK channels in contrast to large primary alcohol of similar size. A functional difference between diols and primary alcohols has been reported previously for NMDA channels32. The addition of a hydroxyl group may lead to decreased sensitivity to inhibition for GIRK channels. The presence of two sites for alcohol modulation also suggests that ascribing a cutoff number for alcohol activation of GIRK channels would not be accurate, in contrast to the determination of the cutoff number for GABAA channels33.
