A regulator that is common to all inwardly rectifying K+ channels is the membrane-bound phospholipid-phosphatidylinositol 4,5-bisphosphate (PIP2) (Huang et al., 1998; Zhang et al., 1999). PIP2 is required for the constitutive basal activity of inward rectifiers like Kir1, Kir2 and Kir3 (GIRK) channels. PIP2 association also underlies agonist-dependent activation of GIRK channels (Huang et al., 1998; Zhang et al., 1999; Xiao et al., 2003). An examination of the relative affinity for PIP2 indicated that GIRK channels interact weakly with PIP2 and Gβγ-dependent activation increases the affinity for PIP2 (Huang et al., 1998; Zhang et al., 1999). High-resolution structural studies indicate that the 5' phosphate in PIP2 is critical for binding to GIRK at the membrane-cytosol interface (Figure 1D) (Whorton and MacKinnon, 2011). Like Gβγ-dependent activation, alcohol-dependent activation also depends on PIP2 interaction with the channel. Alcohol fails to activate GIRK channel in cells where PIP2 levels are depleted using a voltage-activated phosphatase (Dr-VSP) that removes the 5′ phosphate (Bodhinathan and Slesinger, 2013). Moreover, presence of alcohol in the pocket slows down that rate of PIP2 dissociation from the channel, suggesting
