Rationale:
We recently discovered pivotal contributions of stress kinase JNK2 in increased risk of atrial fibrillation (AF) through enhanced diastolic sarcoplasmic reticulum (SR) Ca
2+
leak via ryanodine receptors (RyR2). However, the role of JNK2 in the function of the SR Ca
2+
-ATPase (SERCA2), essential in maintaining [Ca
2+
]
SR
cycling during each heartbeat, is completely unknown.
Objective:
To test the hypothesis that JNK2 increases SERCA2 activity [Ca
2+
]
SR
and exacerbates an arrhythmic [Ca
2+
]
SR
leak-load relationship.
Methods and Results:
We used confocal Ca
2+
imaging in myocytes and HEK cells, biochemistry, dual Ca
2+
/voltage optical mapping in intact hearts from alcohol-exposed or aged mice (where JNK2 is activated). We found that JNK2, but not JNK1, increased SERCA2 uptake and consequently elevated [Ca
2+
]SR load. JNK2 also associates with and phosphorylates SERCA2 proteins. JNK2 causally enhances SERCA2-ATPase activity via increased Vmax, without altering Ca
2+
affinity (Km). Unlike the CaMKII-dependent JNK2 action in SR Ca
2+
leak, JNK2-driven SERCA2 function was CaMKII-independent (not prevented by CaMKII inhibition). With CaMKII blocked, the JNK2-driven SR Ca
2+
loading alone did not significantly raise leak. However, with JNK2-CaMKII-driven SR Ca
2+
leak present, the JNK2-enhanced SR Ca
2+
uptake limited leak-induced reduction in SR Ca
2+
, normalizing Ca
2+
transient amplitude, but at a higher arrhythmogenic SR Ca
2+
leak. JNK2-specific inhibition completely normalized SR Ca
2+
handling, attenuated arrhythmic Ca
2+
activities, and alleviated AF susceptibility in aged and alcohol-exposed myocytes and intact hearts.
Conclusions:
We have identified a novel JNK2-induced activation of SERCA2. The dual-action of JNK2 in CaMKII-dependent arrhythmic SR Ca
2+
leak and a CaMKII-independent uptake exacerbates atrial arrhythmogenicity, while helping to maintain normal levels of Ca
2+
transients and heart function. JNK2 modulation may be a novel therapeutic target for AF prevention and treatment.
JNK2, A Newly-Identified SERCA2 Enhancer, Augments an Arrhythmic [Ca
2+
]
SR
Leak-Load Relationship