In fact, the involvement of changes in affinity between PIP2 and GIRK channels is emerging as a common theme in the activation of GIRK channels by alcohol (Bodhinathan and Slesinger, 2013), Gβγ (Huang et al., 1998; Whorton and MacKinnon, 2013) and Na+ (Ho and Murrell-Lagnado, 1999; Petit-Jacques et al., 1999; Inanobe et al., 2010; Whorton and MacKinnon, 2011). Based on this model of convergence at the PIP2 binding site for these distinct activators, we can highlight certain unanswered points. Alcohol binding at the cytoplasmic domain could structurally re-arrange the PIP2 binding site in a manner that increases the physical retention of PIP2 at this site (Xiao et al., 2003; Whorton and MacKinnon, 2011). One question that remains unanswered is whether the physical rearrangements in the alcohol pocket are inextricably linked to changes in PIP2 binding. Based on the current results, it is unlikely a GIRK mutant will be identified that is deficient in PIP2 binding but has normal alcohol activation. A related question is whether a point mutation will be identified that creates an alcohol resistant GIRK channel that retains
