Alcohol may facilitate a “sliding” movement of the two adjacent GIRK subunits, increasing the affinity for PIP2, and inducing movement of the channel's G loop and transmembrane gates to allow ion permeation (Pegan et al., 2005; Whorton and MacKinnon, 2011, 2013; Mahajan et al., 2013). Increasing the hydrophobicity of the pocket, either by chemical-tagging with an alcohol-like short-chain molecule or by native alcohol itself, lowers the free energy barrier (ΔG) for channel opening (Figure 2), similar to alcohol-sensitive ligand-gated ion channels (LGICs) (Mascia et al., 2000). Alcohol binding to the pocket may produce weak van der Waal and hydrogen bond interactions with several residues in the βD-βE and βL-βM loops that line the pocket of GIRK channels and stabilize an open state, through increasing the PIP2-GIRK affinity. In the alcohol-sensitized GLIC, the B-factor is decreased in the presence of ethanol, suggesting that alcohol also stabilizes an open state (Sauguet et al., 2013). An attractive feature of an allosteric model for gating is that it is compatible with (1). low affinity of GIRK channels for alcohol, (2). low binding energy associated
