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Vol. 59, Issue 2, 225-230, February 2001
Institute of Molecular Cardiobiology, Johns Hopkins University,
Baltimore, Maryland (Y.L., G.R., B.O., E.M., J.S.); and Maryland
Research Laboratories, Otsuka American Pharmaceutical Inc., Rockville,
Maryland (Y.L.)
Many mammalian cells have two distinct types of ATP-sensitive potassium
(KATP) channels: the classic ones in the surface membrane (sKATP) and others in the mitochondrial inner membrane
(mitoKATP). Cardiac mitoKATP channels play a
pivotal role in ischemic preconditioning, and thus represent
interesting drug targets. Unfortunately, the molecular structure of
mitoKATP channels is unknown, in contrast to
sKATP channels, which are composed of a pore-forming
subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). As a means of probing the molecular makeup of
mitoKATP channels, we compared the pharmacology of native
cardiac mitoKATP channels with that of molecularly defined
sKATP channels expressed heterologously in human embryonic
kidney 293 cells. Using mitochondrial oxidation to index
mitoKATP channel activity in rabbit ventricular myocytes,
we found that pinacidil and diazoxide open mitoKATP channels, but P-1075 does not. On the other hand, 5-hydroxydecanoic acid (5HD), but not HMR-1098, blocks mitoKATP channels.
Although pinacidil is a nonselective activator of expressed
sKATP channels, diazoxide did not open channels formed by
Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac
sKATP channels) or Kir6.2/SUR2B. P-1075 activated all the
KATP channels, except Kir6.1/SUR1 channels. Glybenclamide
potently blocked all sKATP channels, but 5HD only blocked
channels formed by SUR1/Kir6.1 or Kir6.2 (IC50s of 66 and
81 µM, respectively). This potency is similar to that for block of
mitoKATP channels (IC50 = 95 µM). In
addition, HMR-1098 potently blocked Kir6.2/SUR2A channels
(IC50 = 1.5 µM), but was 67 times less potent in
blocking Kir6.1/SUR1 channels (IC50 = 100 µM). Our
results demonstrate that mitoKATP channels closely resemble
Kir6.1/SUR1 sKATP channels in their pharmacological profiles.
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