Inhibition of minor intron splicing reduces Na+ and Ca2+ channel expression and function in cardiomyocytes
| Autor: | Auriane C Ernault, Ingeborg van der Made, Simona Casini, Simona Aufiero, Pablo Montañés-Agudo, Carol Ann Remme, Yigal M. Pinto, Esther E. Creemers |
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| Přispěvatelé: | Cardiology, ACS - Heart failure & arrhythmias, APH - Methodology, Amsterdam Cardiovascular Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Calcium Channels
L-Type RNA Splicing chemistry.chemical_element Biology Calcium Splicing Minor spliceosome Gene family Animals Myocytes Cardiac Ion channel Intron retention Voltage-dependent calcium channel Intron Heart Cell Biology Cell Biology and Disease Introns Cell biology Rats chemistry Ion channels RNA splicing Spliceosomes Function (biology) Research Article |
| Zdroj: | Journal of Cell Science article-version (VoR) Version of Record Journal of cell science, 135(1):jcs259191. Company of Biologists Ltd |
| ISSN: | 0021-9533 |
| Popis: | Eukaryotic genomes contain a tiny subset of ‘minor class’ introns with unique sequence elements that require their own splicing machinery. These minor introns are present in certain gene families with specific functions, such as voltage-gated Na+ and voltage-gated Ca2+ channels. Removal of minor introns by the minor spliceosome has been proposed as a post-transcriptional regulatory layer, which remains unexplored in the heart. Here, we investigate whether the minor spliceosome regulates electrophysiological properties of cardiomyocytes by knocking down the essential minor spliceosome small nuclear snRNA component U6atac in neonatal rat ventricular myocytes. Loss of U6atac led to robust minor intron retention within Scn5a and Cacna1c, resulting in reduced protein levels of Nav1.5 and Cav1.2 channels. Functional consequences were studied through patch-clamp analysis, and revealed reduced Na+ and L-type Ca2+ currents after loss of U6atac. In conclusion, minor intron splicing modulates voltage-dependent ion channel expression and function in cardiomyocytes. This may be of particular relevance in situations in which minor splicing activity changes, such as in genetic diseases affecting minor spliceosome components, or in acquired diseases in which minor spliceosome components are dysregulated, such as heart failure. Summary: Knockdown of minor spliceosome component U6atac in cardiomyocytes reveals that expression of the Na+ channel Scn5a and the L-type Ca2+ channel Cacna1c critically depend on minor intron splicing. |
| Databáze: | OpenAIRE |
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