1. Academic Validation
  2. RBM24 controls cardiac QT interval through CaMKIIδ splicing

RBM24 controls cardiac QT interval through CaMKIIδ splicing

  • Cell Mol Life Sci. 2022 Dec 1;79(12):613. doi: 10.1007/s00018-022-04624-4.
Jing Liu # 1 2 3 Ke Wang # 1 Xingyang Liu 4 Lei Pan 1 Wanlu Zhou 1 Jingru Huang 1 Hongli Liu 1 2 Zhiying Su 1 2 Xiu Qin Xu 5 6
Affiliations

Affiliations

  • 1 The Institute of Stem Cell and Regenerative Medicine, School of Medicine, Xiamen University, Xiamen, 361100, Fujian, People's Republic of China.
  • 2 Department of Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361100, People's Republic of China.
  • 3 Shenzhen Research Institute of Xiamen University, Shenzhen, 518000, Guangdong, People's Republic of China.
  • 4 School of Medicine, Xiamen University, Xiamen, 361100, Fujian, People's Republic of China.
  • 5 The Institute of Stem Cell and Regenerative Medicine, School of Medicine, Xiamen University, Xiamen, 361100, Fujian, People's Republic of China. xuxq@xmu.edu.cn.
  • 6 Department of Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361100, People's Republic of China. xuxq@xmu.edu.cn.
  • # Contributed equally.
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.

Keywords

Alternative splicing; Arrhythmia; Calcium; Calmodulin-dependent protein kinase II δ; RNA binding motif 24.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15465
    99.19%, CaMK II Inhibitor‎