In addition to hydrophobicity, molecular volume is also a major determinant of sensitivity to alcohol modulation. Based on the estimated volume of different alcohols that activate GIRK channels and the volume of amino acid side-chains that line the pocket, the GIRK alcohol pocket is estimated to be ~312 Å3 (Bodhinathan and Slesinger, 2013). This volume could optimally accommodate two or three ethanol molecules. By comparison, the alcohol pocket of the GLIC F14′A channel has been estimated to be ~335 Å3 (Howard et al., 2011a), but contained only one bromo-ethanol compound. Future high-resolution crystal structures of alcohol bound to the GIRK alcohol pocket will be needed to determine the precise stoichiometry of ethanol and its stereospecific arrangement within the pocket.
