Calstabin2 - a new target in sudden cardiac death

Sudden cardiac death is occasionally observed in people with structurally normal hearts. Calstabin2 stabilises the ryanodine receptor (RyR)2, preventing aberrant activation of the sarcoplasmic reticulum calcium channel during the resting phase of the cardiac muscle. Calstabin2-deficient mice have structurally normal hearts, but exhibit exercise-induced cardiac ventricular arrhythmias that cause sudden death. In three models of arrhythmias, the calstabin2 stabiliser JTV519 did not prevent arrhythmias in calstabin2(-/-) mice, but reduced the arrhythmias in calstabin2(+/-) mice, illustrating the antiarrhythmic potential of stabilising calstabin2. Familial polymorphic ventricular tachycardia (FPVT) has been linked to three missense mutants (P2328S, Q4201R and V4653F) in the hRyR2 gene of Finnish families. In HEK293 cells, these RyR2 mutants showed less binding of (35)S-calstabin2 than the wild-type, indicating a reduced binding affinity. JTV519 rescues the gain-of-function defect in the RyR2-P2328S channels via increased binding of calstabin2 to the channel complex. In heart failure (HF), there is excessive disassociation of calstabin2 from the RyR2 receptor, and JTV519 has been shown to be beneficial in an animal model of HF. In conclusion, calstabin2 is an important new target in sudden cardiac death associated with either FPVT or HF.