RBM24 controls cardiac QT interval through CaMKIIδ splicing

Calcium/calmodulin-dependent kinase II delta (CaMKII delta) 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 CaMKII delta 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 CaMKII delta are incompletely understood. Here, we show that RNA binding motif protein 24 (RBM24) is a key splicing regulator of CaMKII delta. RBM24 ablation leads to the aberrant shift of CaMKII delta towards the delta-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 CaMKII delta. 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 CaMKII delta to control the cardiac QT interval, highlighting the key role of splicing regulation in cardiac rhythm.

Automated summary

It has been found that RNA binding motif protein 24 (RBM24) is a key regulator of CaMKII delta splicing, playing a crucial role in the heart. Loss of RBM24 leads to abnormal shift of CaMKII delta towards the delta-C isoform, affecting Ca2+ handling and prolonging the ventricular cardiac action potential and QT interval.