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Data from: NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling

Tarasov, Mikhail1; Struckman, Heather L.1; Olgar, Yusuf1; Miller, Alec1; Demirtas, Mustafa1; Bogdanov, Vladimir1; Terentyeva, Radmila1; Soltisz, Andrew M.1; Meng, Xiaolei1; Min, Dennison1; Sakuta, Galina1; Dunlap, Izabella1; Duran, Antonia D.1; Foster, Mark P.1; Davis, Jonathan P.1; Terentyev, Dmitry1; Györke, Sándor1; Veeraraghavan, Rengasayee1; Radwański, Przemysław B.1

Research facility: The Ohio State University
Published May 29, 2023 on Dryad. https://doi.org/10.5061/dryad.jdfn2z3fs

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Abstract

Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCC). 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 NaV dysregulation within transverse (T)-tubules in D96V-CaM-associated arrhythmias. D96V-CaM induces pro-arrhythmic late Na+ current (INa) by impairing inactivation of NaV1.6, but not the predominant cardiac NaV isoform, NaV1.5. We investigated arrhythmia mechanisms using mice with cardiac-specific expression of D96V-CaM (cD96V). Super-resolution microscopy revealed close proximity of NaV1.6 and RyR2 within T-tubules. NaV1.6 density within these regions increased in cD96V relative to WT. Consistent with NaV1.6 dysregulation by D96V-CaM in these regions, we observed increased late NaV activity in T-tubules. The resulting late INa promoted aberrant Ca2+ release and prolonged APD in myocytes, leading to LQT and ventricular tachycardia (VT) in vivo. Cardiac-specific NaV1.6 knockout protected cD96V mice from increased T-tubular late NaV activity, and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promotes arrhythmias by dysregulating LTCC and NaV1.6 within T-tubules and thereby, facilitating aberrant Ca2+ release.