calstabin2 from the RyR2 causes the calcium leak. The depletion of calstabin2 can occur in both heart failure and CPVT. Calstabin2 is a protein that stabilizes RyR2 in its closed state, preventing Ca2+ leakage during diastole. When calstabin2 is lost, the interdomain interactions of RyR2 become loose, allowing the Ca2+ leak. However, the role of calstabin2 has been controversial, as some studies have found it necessary for the effect of JTV-519, whereas others have found the drug functions without the stabilizing protein. Molecular mechanism JTV-519 seems to restore the stable conformation of RyR2 during the closed state. It is still controversial whether or not calstabin2 is necessary for this process, however, many studies believe that JTV-519 can act directly on the channel and by binding, prevents conformational changes. This stabilization of the channel decreases its open probability resulting in fewer leaks of Ca2+ into the cytosol and fewer Ca2+ sparks to occur. Researchers who believe that calstabin2 is necessary for JTV-519 effect, found that this drug may function by inducing the binding of calstabin2 back to the channel or increasing calstabin2's affinity for the RyR2 and thus increasing its stability. References Calcium channel blockers Benzothiazepines Phenol ethers Piperidines