JNK2, a Newly-Identified SERCA2 Enhancer, Augments an Arrhythmic [Ca²⁺]_SR Leak-Load Relationship

We recently discovered pivotal contributions of stress kinase JNK2 (c-Jun N-terminal kinase isoform 2) in increased risk of atrial fibrillation through enhanced diastolic sarcoplasmic reticulum (SR) calcium (Ca²⁺) leak via RyR2 (ryanodine receptor isoform 2). However, the role of JNK2 in the function of the SERCA2 (SR Ca²⁺-ATPase), essential in maintaining SR Ca²⁺ content cycling during each heartbeat, is completely unknown.

To test the hypothesis that JNK2 increases SERCA2 activity SR Ca²⁺ content and exacerbates an arrhythmic SR Ca²⁺ content leak-load relationship.

We used confocal Ca²⁺ imaging in myocytes and HEK-RyR2 (ryanodine receptor isoform 2-expressing human embryonic kidney 293 cells) cells, biochemistry, dual Ca²⁺/voltage optical mapping in intact hearts from alcohol-exposed or aged mice (where JNK2 is activated). We found that JNK2, but not JNK1 (c-Jun N-terminal kinase isoform 1), increased SERCA2 uptake and consequently elevated SR Ca²⁺ content load. JNK2 also associates with and phosphorylates SERCA2 proteins. JNK2 causally enhances SERCA2-ATPase activity via increased maximal rate, without altering Ca²⁺ affinity. Unlike the CaMKII (Ca²⁺/calmodulin-dependent kinase II)-dependent JNK2 action in SR Ca²⁺ leak, JNK2-driven SERCA2 function was CaMKII independent (not prevented by CaMKII inhibition). With CaMKII blocked, the JNK2-driven SR Ca²⁺ loading alone did not significantly raise leak. However, with JNK2-CaMKII-driven SR Ca²⁺ leak present, the JNK2-enhanced SR Ca²⁺ uptake limited leak-induced reduction in SR Ca²⁺, normalizing Ca²⁺ transient amplitude, but at a higher arrhythmogenic SR Ca²⁺ leak. JNK2-specific inhibition completely normalized SR Ca²⁺ handling, attenuated arrhythmic Ca²⁺ activities, and alleviated atrial fibrillation susceptibility in aged and alcohol-exposed myocytes and intact hearts.

We have identified a novel JNK2-induced activation of SERCA2. The dual action of JNK2 in CaMKII-dependent arrhythmic SR Ca²⁺ leak and a CaMKII-independent uptake exacerbates atrial arrhythmogenicity, while helping to maintain normal levels of Ca²⁺ transients and heart function. JNK2 modulation may be a novel therapeutic target for atrial fibrillation prevention and treatment.