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Vol. 59, Issue 5, 1086-1093, May 2001
Department of Physiology II, University of Tübingen,
Tübingen, Germany
Recent work has established membrane phospholipids such as
phosphatidylinositol-4,5-bisphosphate (PIP2) as potent
regulators of KATP channels controlling open probability
and ATP sensitivity. We here investigated the effects of phospholipids
on the pharmacological properties of cardiac type KATP
(Kir6.2/SUR2A) channels. In excised membrane patches KATP
channels showed considerable variability in sensitivity to
glibenclamide and ATP. Application of the phosphatidylinositol phosphates (PIPs) phosphatidylinositiol-4-phosphate,
PIP2, and phosphatidylinositol-3,4,5-trisphosphate reduced
sensitivity to ATP and glibenclamide closely resembling the native
variability. Insertion of the patch back into the oocyte
(patch-cramming) restored high ATP and glibenclamide sensitivity,
indicating reversible modulation of KATP channels via
endogenous PIPs-degrading enzymes. Thus, the observed variability
seemed to result from differences in the membrane phospholipid content.
PIP2 also diminished activation of KATP
channels by the K+ channel openers (KCOs) cromakalim and
P1075. The properties mediated by the sulphonylurea receptor
(sensitivity to sulfonylureas and KCOs) seemed to be modulated by PIPs
via a different mechanism than ATP inhibition mediated by the Kir6.2
subunits. First, polycations abolished the effect of PIP2
on ATP inhibition consistent with an electrostatic mechanism but only
weakly affected glibenclamide inhibition and activation by KCOs.
Second, PIP2 had clearly distinct effects on the
concentration-response curves for ATP and glibenclamide. However, PIPs
seemed to mediate the different effects via the Kir6.2 subunits because
a mutation in Kir6.2 (R176A) attenuated simultaneously the effects of
PIP2 on ATP and glibenclamide inhibition. Finally,
experiments with various lipids revealed structural features necessary
to modulate KATP channel properties and an artificial lipid
(dioleoylglycerol-succinyl-nitriloacetic acid) that mimicked the
effects of PIPs on KATP channels.
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