Direct interactions of phosphatidylinositol-4, 5-bisphosphate (PtdIns (4, 5) P 2) with inwardly rectifying potassium channels are stronger with channels rendered constitutively active by binding to PtdIns (4, 5) P 2, such as IRK1, than with G-protein-gated channels (GIRKs). As a result, PtdIns (4, 5) P 2 alone can activate IRK1 but not GIRKs, which require extra gating molecules such as the βγ subunits of G proteins or sodium ions. Here we identify two conserved residues near the inner-membrane interface of these channels that are critical in interactions with PtdIns (4, 5) P 2. Between these two arginines, a conservative change of isoleucine residue 229 in GIRK4 to the corresponding leucine found in IRK1 strengthens GIRK4–PtdIns (4, 5) P 2 interactions, eliminating the need for extra gating molecules. A negatively charged GIRK4 residue, two positions away from the most strongly interacting arginine, mediates stimulation of channel activity by sodium by strengthening channel–PtdIns (4, 5) P 2 interactions. Our results provide a mechanistic framework for understanding how distinct gating mechanisms of inwardly rectifying potassium channels allow these channels to subserve their physiological roles.