Recently, we described a high resolution structure of the cytoplasmic domains of a G protein-insensitive inwardly rectifying potassium channel (IRK1 or Kir2.1) that contains bound alcohols21. The alcohol, 2-methyl-2,4-pentanediol (MPD), is bound to four similar solvent accessible hydrophobic pockets, each formed by two adjacent subunits of the tetramer. Intriguingly, this IRK1-bound pocket has features similar to the structure of an odorant alcohol binding protein, LUSH, which was crystallized with EtOH22. In both structures, the alcohol pocket is formed by hydrophobic amino acids and hydrogen bonding polar groups. Thus, the hydrophobic alcohol-bound pocket in IRK1 is a putative site for modulation by alcohols. Because the crystal structure of the cytoplasmic domain of GIRK1 or GIRK2 channels is very similar to that of IRK123-25, we hypothesize that GIRK channels also possess cytoplasmic hydrophobic alcohol-binding pockets that are involved in alcohol-dependent activation.
