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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2334-2348
Number of pages15
JournalBiophysical Journal
Volume78
Issue number5
DOIs
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Biophysics

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