Lipid-dependent gating of Kir2 channels. (A) In the absence of any PL⁻s, the two binding sites are unstructured and the CTD is displaced away from the membrane. (B) Binding of PIP₂ at the primary site or of PL⁻ binding at the second site initiates upward movement of the CTD toward the membrane and induces the formation of the other site (white circles). (C) Subsequent binding to the other site places the channel in a preactivated state (D), from which opening is favored.