期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 290, 期 5, 页码 H1770-H1776出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01084.2005
关键词
bilayers; mitochondria; protein kinase C; ischemia; preconditioning
资金
- NHLBI NIH HHS [HL-034708, HL-58691-01] Funding Source: Medline
- NIGMS NIH HHS [P01 GM066730, GM-066730] Funding Source: Medline
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 ( similar to 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 mu M) increased the cumulative open probability of the mitoK(ATP) channel previously inhibited by ATP ( P < 0.05), but its inactive analog 4 alpha-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-delta 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.
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