Figure 2.

Working model of GIRK channel gating. Alcohol binds directly to the alcohol pocket and Gβγ binds very close to the alcohol pocket. The binding leads to multi-domain conformation changes that culminate in stabilization of the PIP₂-bound open state of GIRK channel; involving increase in PIP₂-GIRK affinity (Bodhinathan and Slesinger, 2013) and possibly involving structural changes to the PIP₂ binding site described in Figure 1. In addition, small molecule modulators of GIRK channel can possibly interact with the alcohol binding site, or may directly stabilize PIP₂-bound open state of the GIRK channels. These events lead to the movement and opening of the G loop and the transmembrane gates, the final step of activation leading to K⁺ ion permeation through the GIRK channel pore.