Stimulation of NOX2 in isolated hearts reversibly sensitizes RyR2 channels to activation by cytoplasmic calciumReport as inadecuate

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The response of ryanodine receptor RyR channels to cytoplasmic free calcium concentration Ca2+ is redoxsensitive. Here, we report the effects of a mild oxidative stress on cardiac RyR RyR2 channels in Langendorffperfused rat hearts. Single RyR2 channels fromcontrol ventricles displayed the same three responses to Ca2+ reportedin other mammalian tissues, characterized by low, moderate, or high maximal activation. A single episodeof 5 min of global ischemia, followed by 1 min of reperfusion, enhanced 2.3-fold the activity of NOX2 comparedto controls and changed the frequency distribution of the different responses of RyR2 channels to calcium, favoringthe more active ones: high activity response increased and low activity response decreased with respect tocontrols. This change was fully prevented by perfusion with apocynin or VAS 2870 before ischemia and totallyreversed by the extension of the reperfusion period to 15 min. In vitro activation of NOX2 in control SR vesiclesmimicked the effect of the ischemia-reperfusion episode on the frequencies of emergence of single RyR2 channelresponses to Ca2+ and increased 2.2-fold the rate of calcium release in Ca2+-loaded SR vesicles. In vitro changeswere reversed at the single channel level by DTT and in isolated SR vesicles by glutaredoxin. Our results indicatethat in whole hearts a mild oxidative stress enhances the response of cardiac RyR2 channels to calciumvia NOX2activation, probably by S-glutathionylation of RyR2 protein. This change is transitory and fully reversible, suggestinga possible role of redox modification in the physiological response of cardiac RyR2 to cellular calcium influx.Nota general

Artículo de publicación ISI

Author: Donoso Laurent, Paulina; - Finkelstein Muñoz, José Pablo; - Montecinos, Luis; - Said, Matilde; - Sánchez Vergara, Gina Luisa;



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