The kinetic and physical basis of K-ATP channel gating: Toward a unified molecular understanding

K-ATP channels can be formed from Kir6.2 subunits with or without SUR1. The open-state stability of K-ATP, channels can be increased or reduced by mut ations throughout the Kir6.2 subunit, and is increased by application of PI P, to the cytoplasmic membrane. Increase of open-state stability is manifes ted as an increase in the channel open probability in the absence of ATP (P o-zero) and a correlated decrease in sensitivity to inhibition by ATP. Sing le channel lifetime analyses were performed on wild-type and I154C mutant c hannels expressed with, and without, SUR1, Channel kinetics include a singl e, invariant, open duration; an invariant, brief, closed duration; and long er closed events consisting of a "mixture of exponentials," which are prolo nged in ATP and shortened after PIP, treatment. The steady-state and kineti c data cannot be accounted for by assuming that ATP binds to the channel an d causes a gate to close. Rather, we show that they can be explained by mod els that assume the following regarding the gating behavior: 1) the channel undergoes ATP-insensitive transitions from the open state to a short close d state (C-f) and to a longer-lived closed state (C-o); 2) the C-o state is destabilized in the presence of SUR1; and 3) ATP can access this C-o state , stabilizing it and thereby inhibiting macroscopic currents, The effect of PIP, and mutations that stabilize the open state is then to shift the equi librium of the "critical transition" from the open state to the ATP-accessi ble C-o state toward the O state, reducing accessibility of the C-o state, and hence reducing ATP sensitivity.