Figure 3.

Proposed mechanism by which ATP stimulates the activity of channels formed by E128K-SUR1 and R176E-, R192E- or R206E-Kir6.2. (A) In WT channels SUR1 and Kir6.2 are functionally coupled. This leads to stable interactions between Kir6.2 and PIP₂ and efficient ATP inhibition of channel activity. (B) In E128K-SUR1 + WT Kir6.2 channels, functional coupling between SUR1 and Kir6.2 is disrupted causing unstable Kir6.2-PIP₂ interactions thereby reduced open probability. The uncoupling between SUR1 and Kir6.2 also renders the channel less sensitive to ATP inhibition. (C) In channels formed by E128K-SUR1 and Kir6.2 PIP₂ mutants, most channels are unable to interact with PIP₂ resulting in no channel activity in Kint/EDTA. ATP binding to Kir6.2 causes a conformational change that resets the channel from closed to a “ready to conduct” state such that when ATP unbinds, the channel opens briefly before relapsing into PIP₂-unbound closed state or before ATP rebinds again to close the channel. High concentrations of exogenous PIP₂ can also force the channel to open briefly. Note schemas do not represent quantitative kinetic or structural information.