Similar to GABA-gated ion channels, a physical pocket in the channel with a defined cutoff is postulated to mediate alcohol activation of GIRK channels. That is, alcohols with a carbon chain length up to four carbons (i.e. methanol, ethanol, 1-propanol (1-PrOH) and 1-butanol (1-BuOH)) activate GIRK1/2 heteromeric channels while longer alcohols inhibit the channels7,8. This cutoff effect suggests there are physical constraints, possibly linked to the length or hydrophobicity of the alcohol, that determine the sensitivity to alcohol modulation6,8. However, the molecular mechanism underlying alcohol activation of GIRK channels is not known. Mutagenesis studies of GIRK2 channels have implicated the distal C-terminal cytoplasmic domain in activation by alcohol7,20, but these studies did not reveal a physical alcohol-binding pocket in the channel.
