Fig. 2: Representative diagram illustrating the consequences of RyR2 gain-of-function or loss-of-function heterozygous mutations.

A During diastole, the PKA- or the CaMKII-phosphorylation of the RyR2 gain-of-function mutant channels induces a SR Ca²⁺ leak that increases the diastolic Ca²⁺ concentration and activates the NCX exchanger. This leads to I_Ti current which generates DADs and arrhythmias. B During AP, the I_CaL activates the phosphorylated RyR2-WT channels that generate a normal calcium transient with a lower amplitude which in consequences, induces an accumulation of the residual Ca²⁺ in the SR which gradually increases. When the SR Ca²⁺ load achieves the threshold of stimulation of the phosphorylated RyR2 loss-of-function mutant channels, it releases Ca²⁺. This in turn activates the neighboring RyR2-WT enhancing thus the CICR mechanism. Hence, the Ca²⁺ release through the RyR2 loss-of-function mutant channels at the end of the Ca²⁺ transient induces a second phase of Ca²⁺ release. It activates the NCX exchanger leading to I_Ti current which generates EADs responsible of the pathogenesis of the CPVT syndrome.