Another strategy for treating alcoholism could be to antagonize the direct action of alcohol in the brain through alcohol-selective therapeutics. Understanding the chemical nature of the GIRK alcohol pocket has revealed unique chemical rules that are associated with channel activation. The chemical rules of hydrophobicity and size of the ligand occupying the pocket, have significant implications for the development of chemical therapeutics that can occupy the pocket and selectively prevent alcohol access to GIRK channels. It may be possible to design smart chemicals that do not engage the channel activation mechanism through the pocket but selectively block access to alcohol. Interestingly, numerous synthetic ligands have been reported to modulate GIRK channel function, including antidepressants (Kobayashi et al., 2004, 2011; Hamasaki et al., 2013), antipsychotics (Kobayashi et al., 2000; Heusler et al., 2011), and anesthetics (Slesinger, 2001; Yamakura et al., 2001; Zhou et al., 2001; Styer et al., 2010). Recently, a small compound was described that selectively activates heterotetramers containing the GIRK1 subunit and exhibits anti-epileptic properties (Kaufmann et al., 2013). It is not known where this compound acts, but it offers an opportunity to discover possible antagonists for ethanol-dependent activation.
