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Vol. 59, Issue 2, 225-230, February 2001

Pharmacological Comparison of Native Mitochondrial KATP Channels with Molecularly Defined Surface KATP Channels

Yongge Liu, Guifen Ren, Brian O'Rourke, Eduardo Marbán, and Jegatheesan Seharaseyon

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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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