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Summary Years of extensive research on the activation of G-protein-gated inwardly rectifying potassium (GIRK) channels have elucidated a complex macromolecular signaling framework encompassing both protein modulation (involving G proteins, regulators of G protein signaling [RGS], and sorting nexin 27 [SNX27]) and small molecule modulation (involving membrane lipid phosphatidylinositol 4,5-bisphosphate [PIP 2 ], cholesterol, ethanol, and newly identified compounds) (Figure 1)