Proposed model for the role of E128 in SUR1-Kir6.2 coupling. (A) Cartoon illustrating proposed physical relationships between SUR1, Kir6.2, and PIP₂ in the WT, E128K mutant, and the Kir6.2ΔC36 channels. (B) The E128W mutation destabilizes the channel in the SUR1-Kir6.2–coupled, PIP₂-bound open state, leading to channel inactivation. These structural changes can be overcome by increasing membrane PIP₂ or by ATP binding to the channel that recovers coupling between SUR1 and Kir6.2, allowing channels to enter the PIP₂-bound open state briefly before inactivation occurs again. Note that the four states presented should not be taken as detailed kinetic gating states of the channel, and that the transitions between the states are indicated only to illustrate the recovery effects of PIP₂ and ATP on inactivated channels.