Diadenosine tetraphosphate-gating of cardiac K(ATP) channels requires intact actin cytoskeleton.
Diadenosine polyphosphates (ApnA) have been recently discovered in the heart, and their levels found to be regulated by ischemia. These signaling molecules are believed to regulate cellular processes that alarm a cell to metabolic stress. In particular, changes in cardiac diadenosine polyphosphates (ApnA) levels may contribute to the regulation of ATP-sensitive K+ (K(ATP)) channel activity, an ion channel that couples the cellular metabolic state with membrane excitability. A feature of myocardial ischemia is the disruption of the actin cytoskeleton which critically regulates the behavior of K(ATP) channels. Whether the integrity of actin microfilaments regulates the interaction of ApnA with K(ATP) channels is not known. The inside-out configuration of the patch-clamp technique was applied to cardiomyocytes isolated from guinea-pig heart. Following patch excision, the prototype dinucleotide, diadenosine tetraphosphate (Ap4A), inhibited K(ATP) channel opening. Treatment of the internal side of membrane patches with either cytochalasin B or DNase I, disrupters of the actin cytoskeleton, prevented Ap4A-induced inhibition of K(ATP) channel opening. Application of purified actin to DNase-treated membrane patches restored the ability of Ap4A to close K(ATP) channels. This study shows that inhibition of cardiac K(ATP) channel by Ap4A, a putative alarmone, requires intact subsarcolemmal actin network. Such interaction between K(ATP) channels, the cardiomyocyte cytoskeleton and intracellular Ap4A could affect different channel-dependent functions.
Jovanović
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Department of Internal Medicine, Mayo Clinic, Mayo Foundation, Rochester, MN, USA.
Jovanović
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D000199:Actins / Q000378:metabolism*; D000818:Animals; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects
D000199:Actins; D015226:Dinucleoside Phosphates; D010975:Platelet Aggregation Inhibitors; D015221:Potassium Channels; C020733:diadenosine tetraphosphate