The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding

Biophys J. 2000 May;78(5):2334-48. doi: 10.1016/S0006-3495(00)76779-8.


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 PIP(2) 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 PIP(2) 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 (C(0)); 2) the C(0) state is destabilized in the presence of SUR1; and 3) ATP can access this C(0) state, stabilizing it and thereby inhibiting macroscopic currents. The effect of PIP(2) 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 C(0) state toward the O state, reducing accessibility of the C(0) state, and hence reducing ATP sensitivity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters*
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Biophysical Phenomena
  • Biophysics
  • COS Cells
  • Ion Channel Gating
  • Kinetics
  • Models, Biological
  • Mutagenesis, Site-Directed
  • Phosphatidylinositol 4,5-Diphosphate / pharmacology
  • Potassium Channels / chemistry
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels, Inwardly Rectifying*
  • Protein Structure, Quaternary
  • Receptors, Drug / chemistry
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sulfonylurea Receptors


  • ATP-Binding Cassette Transporters
  • Phosphatidylinositol 4,5-Diphosphate
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Recombinant Proteins
  • Sulfonylurea Receptors
  • Adenosine Triphosphate