JNK2, a Newly-Identified SERCA2 Enhancer, Augments an Arrhythmic [Ca 2+ ] SR Leak-Load Relationship

作者：Jiajie Yan, Dan J. Bare, Jaime DeSantiago, Weiwei Zhao, Yiming Mei, Zhenhui Chen, Kenneth S. Ginsburg, R. John Solaro, Beata M. Wolska, Donald M. Bers, S.R. Wayne Chen, Xun Ai · 发表于：Circulation Research · 年份：2020 · DOI：10.1161/circresaha.120.318409 · 被引用次数：52 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Atrial Fibrillation Management and Outcomes

Rationale: 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 (Ca 2+ ) leak via RyR2 (ryanodine receptor isoform 2). However, the role of JNK2 in the function of the SERCA2 (SR Ca 2+ -ATPase), essential in maintaining SR Ca 2+ content cycling during each heartbeat, is completely unknown. Objective: To test the hypothesis that JNK2 increases SERCA2 activity SR Ca 2+ content and exacerbates an arrhythmic SR Ca 2+ content leak-load relationship. Methods and Results: We used confocal Ca 2+ imaging in myocytes and HEK-RyR2 (ryanodine receptor isoform 2-expressing human embryonic kidney 293 cells) 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 (c-Jun N-terminal kinase isoform 1), increased SERCA2 uptake and consequently elevated SR Ca 2+ content load. JNK2 also associates with and phosphorylates SERCA2 proteins. JNK2 causally enhances SERCA2-ATPase activity via increased maximal rate, without altering Ca 2+ affinity. Unlike the CaMKII (Ca 2+ /calmodulin-dependent kinase II)-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 JNK...