GIRK channels assemble into heterotetramers of GIRK1/2, GIRK1/3, GIRK1/4, or GIRK2/3 subunits or in some cases homotetramers of GIRK2 subunits (Figure 1A) (Luscher and Slesinger, 2010). The alcohol pocket in GIRK channels is located at the interface between two adjoining GIRK subunits in the cytoplasmic domains (Figures 1B,C) (Aryal et al., 2009). Originally, the alcohol pocket was first identified in Kir2.1 channels with the alcohol MPD (Pegan et al., 2006; Aryal et al., 2009). The alcohol pocket is formed by three prominent structural elements: N-terminal domain and βD-βE loop from one subunit and the βL-βM loop from an adjacent subunit (Pegan et al., 2006; Aryal et al., 2009). Through site-directed mutagenesis of amino acids lining the alcohol pocket in GIRK2, Aryal et al. (2009) demonstrated that the alcohol pocket is the site for alcohol-dependent activation of GIRK2 channels. The hydrophobic pocket appears to be conserved within the family of inwardly rectifying potassium channels and across different species (Supplemental Figure S1). The effect of alcohol in the pocket may not produce the same effect on all Kir channels. For example, Kir2
