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 Ca ²⁺ leak. This study investigates the contribution of Ca ²⁺ /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 Ca ²⁺ spark frequency and amplitudes of Ca ²⁺ transients but did not affect SR Ca ²⁺ load. Interestingly, inhibition of both, CaMKII and PKA, attenuated the late I _Na -dependent induction of the SR Ca ²⁺ leak. PKA inhibition additionally reduced the amplitudes of systolic Ca ²⁺ transients. FRET-measurements revealed increased levels of cAMP upon late I _Na augmentation, which could be prevented by simultaneous inhibition of Na ⁺ /Ca ²⁺ -exchanger (NCX) suggesting that PKA is activated by Ca ²⁺ -dependent cAMP-production. Whereas inhibition of PP2A showed no effect on late I _Na -dependent alterations of Ca ²⁺ cycling, additional inhibition of PP1 further increased the SR Ca ²⁺ leak. In line with this, selective activation of PP1 yielded a strong reduction of the late I _Na -induced SR Ca ²⁺ leak and did not affect systolic Ca ²⁺ release. This study indicates that phosphatase/kinase-balance is perturbed upon increased Na ⁺ influx leading to disruption of ventricular Ca ²⁺ 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.