In cardiac muscle cells, each contraction is governed by Ca²⁺ release from intracellular stores, the sarcoplasmic reticulum (SR). The Ca²⁺ release channels, a.k.a. ryanodine receptors (RyRs), are located in the SR membrane and become activated by the Ca²⁺-induced Ca²⁺ release mechanism. The function of these channels can be affected by various posttranslational modifications and by several mutations that were identified recently. Most RyR mutations of the cardiac channel isoform are associated with arrhythmias, often manifest as catecholaminergic polymorphic ventricular tachycardias (CPVTs) induced by emotional stress or physical activity. As a serious complication, these CPVTs can lead to sudden cardiac death (SCD). When heterologously expressed, mutated RyR channels exhibited changes of channel gating resulting in accidental and spontaneous SR Ca²⁺ release and an abnormally sensitive Ca²⁺ dependent activation, both being potentially arrhythmogenic by inducing Ca²⁺ activated depolarizing membrane currents. Like inherited mutations of the channel, acquired modifications of the RyR can also lead to similar functional changes on the molecular level, that assemble into a comparable cellular phenotype. In our studies we characterized EC-coupling and Ca²⁺ signalling in mdx mouse cardiomyocytes, a model of dystrophic cardiomyopathy. Cells were examined using confocal imaging of Ca²⁺ signals, quantification of reactive oxygen species (ROS), in combination with the whole-cell voltage-clamp technique and pharmacological tools. Dystrophic myocytes were found to have hypersensitive Ca²⁺ signalling and elevated EC-coupling gain, but also showed more pronounced ROS generation, particularly after mechanical stress (Jung et al., 2008). Many of the Ca²⁺ signaling disturbances could be corrected by reducing agents (e.g. MPG), by superoxide dismutase (SOD) mimetics or by inhibitors of ROS generating NAD(P)H oxidases. Taken together, our findings suggest that the RyR hypersensitivity in dystrophic cardiomyocytes may result from redox modifications of the channel proteins. These and related observations indicate that malfunctions of intracellular Ca²⁺ release channels are one of the cornerstones of cardiac Ca²⁺ signalling abnormalities and underlie some types of arrhythmias, therefore rendering them attractive as future drug targets. The simultaneous presence or activation of several of these channel sensitizing mechanisms, such as RyR oxidation combined with β-adrenergic stimulation, possibly with subsequent phosphorylation of the RyRs, may be particularly detrimental.