KCNJ6 encodes the G protein-gated inwardly rectifying potassium channel subunit 2 (GIRK2), which, when assembled into a GIRK channel, plays a role in regulating cell excitability [13]. The inward rectifying properties of GIRK are based on the ability to conduct potassium ions into the cell more easily than out, leading to a reduction in excitability [14, 15]. GIRK function in neurons is associated with activation of G protein-coupled receptors (GPCRs), which leads to dissociation of Gβγ subunits from the G protein complex and binding to the channel [16]. In addition, this family of GIRK channels can be potentiated by ethanol concentrations (20–50 mM) relevant to human alcohol usage through direct interaction with a hydrophobic pocket on the channel [17, 18]. Studies in model organisms also reveal the importance of GIRK function in AUD: mice lacking GIRK2 demonstrate reduced ethanol analgesia, greater ethanol-stimulated activity in open-field tests, increased self-administration of ethanol, and failure to develop a conditioned place preference for ethanol [19–21]. Thus, GIRK channels not only modulate the excitability of the neurons but also play an essential role in regulating responses to alcohol.
