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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/H1770    most recent 01084.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Jiang, M. T. Articles by Bosnjak, Z. J. Search for Related Content PubMed PubMed Citation Articles by Jiang, M. T. Articles by Bosnjak, Z. J.

Characterization of human cardiac mitochondrial ATP-sensitive potassium channel and its regulation by phorbol ester in vitro

Departments of ¹Anesthesiology, ²Physiology, ³Surgery, and ⁴Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 13 October 2005 ; accepted in final form 15 December 2005

Activation of the mitochondrial ATP-sensitive K⁺ channel (mitoK_ATP) and its regulation by PKC are critical events in preconditioning induced by ischemia or pharmaceutical agents in animals and humans. The properties of the human cardiac mitoK_ATP channel are unknown. Furthermore, there is no evidence that cytosolic PKC can directly regulate the mitoK_ATP 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 mitoK_ATP 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 (150 mM). The conductance of native mitoK_ATP 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 mitoK_ATP channel is activated by diazoxide and inhibited by ATP and 5-HD. The PKC activator phorbol 12-myristate 13-acetate (2 µM) increased the cumulative open probability of the mitoK_ATP channel previously inhibited by ATP (P < 0.05), but its inactive analog 4-phorbol 12,13-didecanoate had no effect. Western blot analysis detected an inward rectifying K⁺ channel (Kir6.2) immunoreactive protein at 56 kDa and PKC- in the IMM. These data provide the first characterization of the human cardiac mitoK_ATP 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/pharmacological preconditioning.

bilayers; mitochondria; protein kinase C; ischemia; preconditioning

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