When exercise is deadly

We all know that exercise is good for us, but there are times when it can be deadly. Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) experience exercise-induced arrhythmias, which can lead to sudden cardiac death in structurally normal hearts. But what triggers these fatal arrhythmias? In Cell, Marks and colleagues now report that the problem might be a 'leaky' Ca²⁺-release channel (the tetrameric ryanodine receptor, RyR2), which is mutated in CPVT patients.

During exercise, increased cyclic AMP levels in cardiac muscle activate cAMP-dependent protein kinase A (PKA). PKA then phosphorylates RyR2, which is on the sarcoplasmic reticulum, and this results in Ca²⁺ release and muscle contraction. The FK506-binding protein (FKBP12.6) — which binds non-phosphorylated RyR2 (one FKBP12.6 per RyR2 monomer) — stabilizes RyR2 to prevent Ca²⁺ release during the resting phase of the cardiac cycle (diastole).

The authors first examined FKBP12.6^−/− mice, and found that their hearts were structurally normal and that, at rest, these mice had no arrhythmias. However, under exercise conditions, FKBP12.6^−/− mice consistently had ventricular arrhythmias similar to those seen in CPVT patients.

Next, Marks and co-workers showed that, although RyR2 was PKA phosphorylated to the same level in FKBP12.6^+/+ and FKBP12.6^−/− mice during exercise, RyR2 channels were more likely to be open in FKBP12.6^−/− mice. In fact, RyR2 channels in FKBP12.6^−/− mice are likely to be open during diastole, when they should be preventing Ca²⁺ release.

So, could this defective Ca²⁺ release be occurring in CPVT patients? The authors studied RyR2 channels containing CPVT-causing mutations, and found that, under rest conditions, these channels had wild-type properties. However, under exercise conditions, when the mutant channels were PKA phosphorylated, they were more likely to be open than wild-type channels. Furthermore, compared with wild-type channels, the mutant channels had a significantly decreased affinity for FKBP12.6.

Finally, Marks and colleagues showed that a mutant form of FKBP12.6, which can bind PKA-phosphorylated RyR2, could restore the normal function of a CPVT-mutant RyR2 channel and of RyR2 channels in FKBP12.6^−/− mouse hearts. So, this work showed that, although a partial depletion of FKBP12.6 from phosphorylated RyR2 needs to occur to allow increased muscle contraction during exercise, too little FKBP12.6 in the RyR2 complex — in FKBP12.6^−/− mice or CPVT patients — results in leaky RyR2 channels that can trigger fatal cardiac arryhthmias.