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RBM24 controls cardiac QT interval through CaMKIIδ splicing

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Abstract

Calcium/calmodulin-dependent kinase II delta (CaMKIIδ) is the predominant cardiac isoform and it is alternatively spliced to generate multiple variants. Variable variants allow for distinct localization and potentially different functions in the heart. Dysregulation of CaMKIIδ splicing has been demonstrated to be involved in the pathogenesis of heart diseases, such as cardiac hypertrophy, arrhythmia, and diastolic dysfunction. However, the mechanisms that regulate CaMKIIδ are incompletely understood. Here, we show that RNA binding motif protein 24 (RBM24) is a key splicing regulator of CaMKIIδ. RBM24 ablation leads to the aberrant shift of CaMKIIδ towards the δ-C isoform, which is known to activate the L-type Ca current. In line with this, we found marked alteration in Ca2+ handling followed by prolongation of the ventricular cardiac action potential and QT interval in RBM24 knockout mice, and these changes could be attenuated by treatment with an inhibitor of CaMKIIδ. Importantly, knockdown of RBM24 in human embryonic stem cell-derived cardiomyocytes showed similar electrophysiological abnormalities, suggesting the important role of RBM24 in the human heart. Thus, our data suggest that RBM24 is a critical regulator of CaMKIIδ to control the cardiac QT interval, highlighting the key role of splicing regulation in cardiac rhythm.

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Data availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Xiao Yang (Beijing Institute of Lifeomics) for the kind donation of αMhc-Cre knockin mouse and Maria Grazia Romanelli (University of Verona) for her kind donation of the GFP-RBM20 plasmid. We are thankful to all members of the Institute of Stem Cell and Regenerative Medicine (School of Medicine, Xiamen University).

Funding

This work was supported by the National Key R&D program of China (2018YFA0107304), National Natural Science Foundation of China (NSFC) (82070424 and 81871744), Natural Science Foundation of Fujian Province (2021J01011), Guangdong Natural Science Foundation (2017A030313113), and the Fundamental Research Funds for the Central Universities (20720220058).

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  1. Jing Liu and Ke Wang contributed equally to this work.

Authors and Affiliations

  1. The Institute of Stem Cell and Regenerative Medicine, School of Medicine, Xiamen University, Xiamen, 361100, Fujian, People’s Republic of China

    Jing Liu, Ke Wang, Lei Pan, Wanlu Zhou, Jingru Huang, Hongli Liu, Zhiying Su & Xiu Qin Xu

  2. Department of Gynecology, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361100, People’s Republic of China

    Jing Liu, Hongli Liu, Zhiying Su & Xiu Qin Xu

  3. Shenzhen Research Institute of Xiamen University, Shenzhen, 518000, Guangdong, People’s Republic of China

    Jing Liu

  4. School of Medicine, Xiamen University, Xiamen, 361100, Fujian, People’s Republic of China

    Xingyang Liu

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  1. Jing Liu
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Contributions

JL designed and executed experiments, analyzed data, provided financial support and wrote the manuscript; KW, XL, LP, WZ, and JH executed experiments and analyzed data; HL and ZS provided resource and administration support; XQX designed the research, analyzed data, provided financial support and wrote the manuscript.

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Correspondence to Xiu Qin Xu.

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Liu, J., Wang, K., Liu, X. et al. RBM24 controls cardiac QT interval through CaMKIIδ splicing. Cell. Mol. Life Sci. 79, 613 (2022). https://doi.org/10.1007/s00018-022-04624-4

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