k201-compound and Death--Sudden--Cardiac

Calstablin2 stabilises the ryanodine receptor (RyR2), preventing aberrant activation of the channels during the resting phase of the cardiac muscle. Loss of this stabilisation may be associated with cardiac arrhythmias, the sudden death occasionally observed in people with structurally normal hearts, as well as the atrial fibrillation in heart failure. Calstabin2-deficient mice have structurally normal hearts but exhibit exercise-induced cardiac ventricular arrhythmias that cause sudden death. In 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 calstablin2. Familial polymorphic ventricular tachycardia in humans has been linked to missense mutants in the hRyR2 gene. In HEK293 cells, these RyR2 mutants showed less binding of 35S-calstabin2 than the wild type, indicating a reduced binding affinity. In human atrial fibrillation and heart failure, where there is excessive disassociation of calstabin2 from the RyR2 receptor in vitro, JTV519 is able to reverse this. In conclusion, calstabin2 is an important new target in sudden cardiac death associated with structurally normal hearts, and in the treatment of atrial fibrillation and heart failure.

Topics: Animals; Cardiovascular Agents; Death, Sudden, Cardiac; Diltiazem; Humans; Tacrolimus Binding Proteins; Thiazepines

Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor-calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.

Topics: Animals; Anti-Arrhythmia Agents; Calcium; Calcium-Transporting ATPases; Cell Line; Cyclic AMP-Dependent Protein Kinases; Death, Sudden, Cardiac; Electric Stimulation; Electrocardiography; Heart; Humans; Isoproterenol; Mice; Myocardial Contraction; Phosphorylation; Physical Exertion; Protein Binding; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tachycardia, Ventricular; Tacrolimus Binding Proteins; Thiazepines

Familial polymorphic ventricular tachycardia (FPVT) is characterized by exercise-induced arrhythmias and sudden cardiac death due to missense mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release channel required for excitation-contraction coupling in the heart.. Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur in Finnish families, result in similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the fight-or-flight stress response. We simulated the effects of exercise on mutant RyR2 channels using protein kinase A (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of-function defect consistent with leaky Ca2+ release channels and a significant rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50). Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to RyR2 and normalized channel function.. Sympathetic activation during exercise induces ventricular arrhythmias above a threshold heart rate in RyR2 mutation carriers. Simulating the downstream effects of the sympathetic activation by PKA phosphorylation of RyR2 channels containing these FPVT missense mutations produced a consistent gain-of-function defect. RyR2 function and calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients.

Topics: Adult; Amino Acid Substitution; Calcium; Cyclic AMP-Dependent Protein Kinases; Death, Sudden, Cardiac; Finland; Genes, Dominant; Humans; Inhibitory Concentration 50; Ion Transport; Magnesium; Middle Aged; Mutation, Missense; Patch-Clamp Techniques; Phosphorylation; Physical Exertion; Point Mutation; Protein Binding; Protein Processing, Post-Translational; Protein Subunits; Recombinant Fusion Proteins; Ryanodine Receptor Calcium Release Channel; Structure-Activity Relationship; Tachycardia, Ventricular; Tacrolimus Binding Proteins; Thiazepines