NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.
NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.
复制标题
DOI：
10.1172/jci152071
复制
发表时间：
2023-04-03
影响因子：
15.9
通讯作者：
Radwanski, Przemyslaw B.
中科院分区：
文献类型：
--
作者：
Tarasov, Mikhail;Struckman, Heather L.;Olgar, Yusuf;Miller, Alec;Demirtas, Mustafa;Bogdanov, Vladimir;Terentyeva, Radmila;Soltisz, Andrew M.;Meng, Xiaolei;Min, Dennison;Sakuta, Galina;Dunlap, Izabella;Duran, Antonia D.;Foster, Mark P.;Davis, Jonathan P.;Terentyev, Dmitry;Veeraraghavan, Rengasayee;Gyorke, Sandor;Radwanski, Przemyslaw B.
钙调蛋白 (CaM) 在心肌细胞中发挥着关键作用，调节 Na+ (NaV) 和 L 型 Ca2+ 通道 (LTCC)。突变 CaM 导致的 LTCC 失调与动作电位持续时间 (APD) 延长和致心律失常性长 QT (LQT) 综合征有关。有趣的是，D96V-CaM 比其他 LQT 相关 CaM 更能延长 APD，尽管它诱导了相当水平的 LTCC 功能障碍，这表明其他去极化通道的失调。在这里，我们提供的证据表明 D96V-CaM 相关心律失常中横管 (T) 内 NaV 失调。 D96V-CaM 通过损害 NaV1.6 的失活而诱导致心律失常的晚 Na+ 电流 (INa)，但不损害主要的心脏 NaV 亚型 NaV1.5。我们使用心脏特异性表达 D96V-CaM (cD96V) 的小鼠研究了心律失常机制。超分辨率显微镜显示 T 管内 NaV1.6 和 RyR2 非常接近。相对于 WT 小鼠，cD96V 中这些区域内的 NaV1.6 密度有所增加。与这些区域中 D96V-CaM 引起的 NaV1.6 失调一致，我们观察到 T 管中晚期 NaV 活性增加。由此产生的晚期 INa 促进了肌细胞异常 Ca2+ 释放并延长了 APD，导致体内 LQT 和室性心动过速。心脏特异性 NaV1.6 KO 可保护 cD96V 小鼠免受 T 管晚期 NaV 活性增加及其致心律失常后果的影响。总之，我们证明 D96V-CaM 通过调节 T 管内的 LTCC 和 NaV1.6 从而促进异常的 Ca2+ 释放来促进心律失常。
Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ 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 NaV dysregulation within transverse (T) tubules in D96V-CaM–associated arrhythmias. D96V-CaM induced a proarrhythmic 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 mice. 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 in vivo. Cardiac-specific NaV1.6 KO protected cD96V mice from increased T-tubular late NaV activity and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promoted arrhythmias by dysregulating LTCCs and NaV1.6 within T-tubules and thereby facilitating aberrant Ca2+ release.
影响因子：
4
作者：
Radwański PB;Johnson CN;Györke S;Veeraraghavan R
通讯作者：
Veeraraghavan R