Biophys J, May 2000, p. 2334-2348, Vol. 78, No. 5

The Kinetic and Physical Basis of K_ATP Channel Gating: Toward a Unified Molecular Understanding

D. Enkvetchakul,^* G. Loussouarn, E. Makhina, S. L. Shyng, and C. G. Nichols

 ^*Division of Renal Medicine and  Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 USA

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 mutations throughout the Kir6.2 subunit, and is increased by application of PIP₂ to the cytoplasmic membrane. Increase of open-state stability is manifested as an increase in the channel open probability in the absence of ATP (Po_zero) and a correlated decrease in sensitivity to inhibition by ATP. Single channel lifetime analyses were performed on wild-type and I154C mutant channels expressed with, and without, SUR1. Channel kinetics include a single, invariant, open duration; an invariant, brief, closed duration; and longer closed events consisting of a "mixture of exponentials," which are prolonged in ATP and shortened after PIP₂ treatment. The steady-state and kinetic data cannot be accounted for by assuming that ATP binds to the channel and causes a gate to close. Rather, we show that they can be explained by models that assume the following regarding the gating behavior: 1) the channel undergoes ATP-insensitive transitions from the open state to a short closed state (C_f) and to a longer-lived closed state (C₀); 2) the C₀ state is destabilized in the presence of SUR1; and 3) ATP can access this C₀ state, stabilizing it and thereby inhibiting macroscopic currents. The effect of PIP₂ and mutations that stabilize the open state is then to shift the equilibrium of the "critical transition" from the open state to the ATP-accessible C₀ state toward the O state, reducing accessibility of the C₀ state, and hence reducing ATP sensitivity.

Biophys J, May 2000, p. 2334-2348, Vol. 78, No. 5
© 2000 by the Biophysical Society   0006-3495/00/05/2334/15  $2.00

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