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Kir6.2 limits Ca^sup 2+^ overload and mitochondrial oscillations of ventricular myocytes in response to metabolic stress
Ist Teil von
American journal of physiology. Heart and circulatory physiology, 2013-11, Vol.305 (10), p.H1508
Ort / Verlag
Bethesda: American Physiological Society
Erscheinungsjahr
2013
Link zum Volltext
Quelle
EZB Free E-Journals
Beschreibungen/Notizen
ATP-sensitive K+ (K...) channels are abundant membrane proteins in cardiac myocytes that are directly gated by intracellular ATP and form a signaling complex with metabolic enzymes, such as creatine kinase. K... channels are known to be essential for adaption to cardiac stress, such as ischemia; however, how all the molecular components of the stress response interact is not fully understood. We examined the effects of decreasing the K... current density on Ca2+ and mitochondrial homeostasis and ischemic preconditioning. Acute knockdown of the pore-forming subunit, Kir6.2, was achieved using adenoviral delivery of short hairpin RNA targeted to Kir6.2. The acute nature of the knockdown of Kir6.2 accurately shows the effects of Kir6.2 depletion without any compensatory effects that may arise in transgenic studies. We also investigated the effect of reducing the K... current while maintaining K... channel protein in the sarcolemmal membrane using a nonconducting Kir6.2 construct. Only 50% K... current remained after Kir6.2 knockdown, yet there were profound effects on myocyte responses to metabolic stress. Kir6.2 was essential for cardiac myocyte Ca2+ homeostasis under both baseline conditions before any metabolic stress and after metabolic stress. Expression of nonconducting Kir6.2 also resulted in increased Ca2+ overload, showing the importance of K+ conductance in the protective response. Both ischemic preconditioning and protection during ischemia were lost when Kir6.2 was knocked down. K... current density was also important for the mitochondrial membrane potential at rest and prevented mitochondrial membrane potential oscillations during oxidative stress. K... channel density is important for adaption to metabolic stress. (ProQuest: ... denotes formulae/symbols omitted.)