Another ion channel with notable ethanol sensitivity is the G-protein-coupled inwardly rectifying K+ channel (GIRK). Ethanol enhances GIRK channel function (Bodhinathan and Slesinger, 2013; Glaaser and Slesinger, 2017), and genetic studies have identified a 43-amino-acid C-terminal region that is crucial for this action of ethanol (Lewohl et al., 1999). Mice carrying a missense mutation in the GIRK channel showed a loss of ethanol-induced analgesia (Kobayashi et al., 1999), and GIRK3 subunit knockout mice showed ethanol conditioned place preference, which was absent in controls (Tipps et al., 2016). Using a crystal structure of a mouse inward rectifier containing a bound ethanol molecule and structure-based mutagenesis, investigators probed a putative hydrophobic ethanol-binding pocket in the cytoplasmic domains of GIRK channels (Aryal et al., 2009).
