FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death

Abstract

Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca(2+) release and cardiac contractility. FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

“…Cells from these animals have delayed afterdepolarizations in the presence of ␤ stimulation. 15 That study focused on the hypothesis that the effects of ␤-adrenergic stimulation were caused by phosphorylation of the RyR. However, in light of the present data, one should consider a role for effects on SERCA activity and/or the L-type current as well as on SR content.…”

“…15,37 It is therefore important to consider whether the effects of isoproterenol are attributable to (1) an increase of SR Ca 2ϩ content or (2) an effect on the RyR. The discussion above argues that the effect on SR content is very important but does not exclude a role for an effect on the RyR.…”

“…It has also been suggested that in heart failure, the open probability (P o ) of the normal RyR may be increased by protein kinase A-dependent phosphorylation and that this may be arrhythmogenic. 15 However, the regulatory protein of the SR Ca 2ϩ -ATPase (SERCA) phospholamban is also a target for protein kinase A, and this work has not distinguished between the roles of (1) changes of RyR properties and (2) change of SR Ca 2ϩ content in arrhythmogenesis. Although, acute sensitization of the RyR produces an abrupt Ca 2ϩ release from the SR, prolonged exposure does not result in diastolic waves of Ca 2ϩ release.…”

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

“…Further, alterations in calcium signaling through ryanodine receptor mutations have been shown to cause sudden cardiac death and catecholaminergic polymorphic ventricular tachycardia. Therefore, calcium signaling irregularities might be a component of the frequent sudden cardiac death seen in HCM [2,[43][44][45][46][47].…”

Targeting ryanodine receptors for anti-arrhythmic therapy

“…Thus, physiologic control of Ca 2+ release from the SR is necessary for timely contraction and relaxation during the cardiac cycle. Pathological "leak" of Ca 2+ during diastole may be detrimental and lead to cardiac arrhythmias [4,5] .…”