Increased late sodium current (late I_Na) is an important arrhythmogenic trigger in cardiac disease. It prolongs cardiac action potential and leads to an increased SR Ca²⁺ leak. This study investigates the contribution of Ca²⁺/Calmodulin-dependent kinase II (CaMKII), protein kinase A (PKA) and conversely acting protein phosphatases 1 and 2A (PP1, PP2A) to this subcellular crosstalk. Augmentation of late I_Na (ATX-II) in murine cardiomyocytes led to an increase of diastolic Ca²⁺ spark frequency and amplitudes of Ca²⁺ transients but did not affect SR Ca²⁺ load. Interestingly, inhibition of both, CaMKII and PKA, attenuated the late I_Na-dependent induction of the SR Ca²⁺ leak. PKA inhibition additionally reduced the amplitudes of systolic Ca²⁺ transients. FRET-measurements revealed increased levels of cAMP upon late I_Na augmentation, which could be prevented by simultaneous inhibition of Na⁺/Ca²⁺-exchanger (NCX) suggesting that PKA is activated by Ca²⁺-dependent cAMP-production. Whereas inhibition of PP2A showed no effect on late I_Na-dependent alterations of Ca²⁺ cycling, additional inhibition of PP1 further increased the SR Ca²⁺ leak. In line with this, selective activation of PP1 yielded a strong reduction of the late I_Na-induced SR Ca²⁺ leak and did not affect systolic Ca²⁺ release. This study indicates that phosphatase/kinase-balance is perturbed upon increased Na⁺ influx leading to disruption of ventricular Ca²⁺ cycling via CaMKII- and PKA-dependent pathways. Importantly, an activation of PP1 at RyR2 may represent a promising new toehold to counteract pathologically increased kinase activity.