TY - JOUR
T1 - The kinetic and physical basis of K(ATP) channel gating
T2 - Toward a unified molecular understanding
AU - Enkvetchakul, D.
AU - Loussouarn, G.
AU - Makhina, E.
AU - Shyng, S. L.
AU - Nichols, C. G.
N1 - Funding Information:
This work was supported by Grant HL45742 from the National Institutes of Health (to C.G.N.), a career development grant from the American Diabetes Association (to S.L.S.), and a Fellowship from the American Heart Association (Missouri Affiliate, to G.L.).
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
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U2 - 10.1016/S0006-3495(00)76779-8
DO - 10.1016/S0006-3495(00)76779-8
M3 - Article
C2 - 10777731
AN - SCOPUS:0034027490
SN - 0006-3495
VL - 78
SP - 2334
EP - 2348
JO - Biophysical Journal
JF - Biophysical Journal
IS - 5
ER -