RBM24 controls cardiac QT interval through CaMKIIδ splicing.
Cell Mol Life Sci
; 79(12): 613, 2022 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-36454480
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
RNA Splicing
/
Heart Diseases
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Mol Life Sci
Journal subject:
BIOLOGIA MOLECULAR
Year:
2022
Document type:
Article