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Na(V)1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling
Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na(+) (Na(V)) and L-type Ca(2+) channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD m...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10065082/ https://www.ncbi.nlm.nih.gov/pubmed/36821382 http://dx.doi.org/10.1172/JCI152071 |
Sumario: | Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na(+) (Na(V)) and L-type Ca(2+) channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels. Here, we provide evidence implicating Na(V) dysregulation within transverse (T) tubules in D96V-CaM–associated arrhythmias. D96V-CaM induced a proarrhythmic late Na(+) current (I(Na)) by impairing inactivation of Na(V)1.6, but not the predominant cardiac Na(V) isoform Na(V)1.5. We investigated arrhythmia mechanisms using mice with cardiac-specific expression of D96V-CaM (cD96V). Super-resolution microscopy revealed close proximity of Na(V)1.6 and RyR2 within T-tubules. Na(V)1.6 density within these regions increased in cD96V relative to WT mice. Consistent with Na(V)1.6 dysregulation by D96V-CaM in these regions, we observed increased late Na(V) activity in T-tubules. The resulting late I(Na) promoted aberrant Ca(2+) release and prolonged APD in myocytes, leading to LQT and ventricular tachycardia in vivo. Cardiac-specific Na(V)1.6 KO protected cD96V mice from increased T-tubular late Na(V) activity and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promoted arrhythmias by dysregulating LTCCs and Na(V)1.6 within T-tubules and thereby facilitating aberrant Ca(2+) release. |
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