In addition to neurotransmitters that activate GIRK channels via GPCRs, alcohol directly opens GIRK channels at concentrations relevant to human consumption (18 mM ethanol or 0.08% blood alcohol level) (Kobayashi et al., 1999; Lewohl et al., 1999; Aryal et al., 2009). Several laboratories have investigated whether ethanol targets GIRK channels in the brain. First, ethanol enhances GIRK currents in VTA neurons (Federici et al., 2009), where they modify the activity of the VTA neural circuit (Michaeli and Yaka, 2010; Padgett et al., 2012). Second, some of analgesic effects of alcohol were found to involve GIRK channels (Ikeda et al., 2002; Blednov et al., 2003). Third, mice lacking GIRK2 channels consume more ethanol and fail to develop conditioned place preference for ethanol when compared to their wild type littermates (Blednov et al., 2001; Hill et al., 2003). Lastly, quantitative trait loci (QTL) mapping identified the GIRK3 subunit in a 0.44 MB region of chromosome 1 that was associated with withdrawal effects following chronic and acute alcohol exposure (Kozell et al., 2009; Ehlers et al., 2010). Taken together, these studies highlight the significance of GIRK channels in the pathophysiology of alcohol consumption and addiction.
