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1 Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
2 Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
3 Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
4 Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: mtjiang{at}mcw.edu.
Activation of the mitochondrial ATP-sensitive potassium channel (mitoKATP) and its regulation by PKC are critical events in preconditioning which is induced by ischemia or pharmaceutical agents in animals and humans. The properties of the human cardiac mitoKATP channel are unknown. Furthermore, there is no evidence that cytosolic PKC can directly regulate the mitoKATP channel located in the inner mitochondrial membrane (IMM), due to the physical barrier of the outer mitochondrial membrane. In the present study, we characterized the human cardiac mitoKATP channel and its potential regulation by PKC associated with the IMM. IMM fractions isolated from human left ventricles were fused into lipid bilayers in symmetrical potassium glutamate solution (150 mM). The conductance of native mitoKATP channels was usually below 80 pS (~70%), which was reduced by ATP and 5-hydroxydecanoic acid (5-HD) in a dose- and time- dependent manner. The native mitoKATP channel is activated by diazoxide and inhibited by ATP and 5-HD. The PKC activator, phorbol 12-myristate-13-acetate (PMA, 2 µM), increased the cumulative open probability of the mitoKATP channel which was previously inhibited by ATP (P<0.05), but its inactive analogue 4
-phorbol-12,13-didecanoate had no effect. Western blot detected a Kir6.2 immunoreactive protein at 56 kDa and PKC-
in the IMM. These data provide the first characterization of the human cardiac mitoKATP channel and its regulation by PKC(s) in IMM. This local PKC control mechanism may represent an alternative pathway to that proposed previously for cytosolic PKC during ischemic and pharmacological preconditioning.
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