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Vol. 55, Issue 6, 1000-1005, June 1999
Section of Molecular and Cellular Cardiology, Department of
Medicine, The Johns Hopkins University School of Medicine, Baltimore,
Maryland
A variety of direct and indirect techniques have revealed the existence
of ATP-sensitive potassium (KATP) channels in the inner
membranes of mitochondria. The molecular identity of these mitochondrial KATP (mitoKATP) channels remains
unclear. We used a pharmacological approach to distinguish
mitoKATP channels from classical, molecularly defined
cardiac sarcolemmal KATP (surfaceKATP) channels
encoded by the sulfonylurea receptor SUR2A and the pore-forming subunit
Kir6.2. SUR2A and Kir6.2 were expressed in
human embryonic kidney (HEK)293 cells, and their activities were
measured by patch-clamp recordings of membrane current.
SurfaceKATP channels are activated potently by 100 µM
pinacidil but only weakly by 100 µM diazoxide; in addition, they are
blocked by 10 µM glibenclamide, but are insensitive to 500 µM
5-hydroxydecanoate. This pharmacology, which was confirmed with
patch-clamp recordings in intact rabbit ventricular myocytes, contrasts
with that of mitoKATP channels as indexed by flavoprotein
oxidation. MitoKATP channels in myocytes are activated equally by 100 µM diazoxide and 100 µM pinacidil. In contrast to
its lack of effect on surfaceKATP channels,
5-hydroxydecanoate is an effective blocker of mitoKATP
channels. Glibenclamide's effects on mitoKATP channels are
difficult to assess, because it independently activates flavoprotein
fluorescence, consistent with a previously described primary uncoupling
effect. Confocal imaging of the subcellular distribution of expressed
fluorescent Kir6.2 in HEK cells and in myocytes revealed no
targeting of mitochondrial membranes. The differences in drug
sensitivity and subcellular localization indicate that
mitoKATP channels are distinct from surface
KATP channels at a molecular level.
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