Impaired Ca(V)1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8.
Impaired Ca(V)1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8.
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DOI：
10.1016/j.yjmcc.2022.10.003
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发表时间：
2022-12
影响因子：
5
通讯作者：
Dick, Ivy E.
中科院分区：
文献类型：
--
作者：
Bamgboye, Moradeke A.;Traficante, Maria K.;Owoyemi, Josiah;DiSilvestre, Deborah;Vieira, Daiana C. O.;Dick, Ivy E.
CaV1.2 L型钙通道的突变可导致一种严重的长QT综合征，称为长QT 8型（LQT 8），导致心律失常，在儿童早期往往是致命的。越来越多的CaV1.2中的这种致病性突变已经被确定，增加了对靶向治疗的需求。由于其中许多突变会减少通道失活;导致动作电位期间过量的Ca 2+进入，钙通道阻滞剂（CCB）似乎代表了一种有希望的治疗选择。然而，CCB在LQT 8的治疗中并不成功。在这里，我们证明这种缺乏疗效可能源于突变对CaV1.2通道失活的影响。由于已知CCB优先结合通道的失活状态，失活中的突变依赖性缺陷导致突变通道的使用依赖性阻断减少。此外，将CCB维拉帕米应用于来自LQT 8患者的诱导多能干细胞（iPSC）衍生的心肌细胞表明，这种使用依赖性阻滞的丧失转化为缺乏纠正LQT表型的功效。随着越来越多的通道病变突变显示出对通道失活的影响，依赖于状态依赖性阻断剂可能会使越来越多的患者没有可行的治疗选择。这种对失活缺陷和状态依赖性阻滞之间相互作用的生物物理学理解可能为指导改进疗法的发展提供新的途径。
Mutations in the CaV1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as long-QT type 8 (LQT8), which results in cardiac arrhythmias that are often fatal in early childhood. A growing number of such pathogenic mutations in CaV1.2 have been identified, increasing the need for targeted therapies. As many of these mutations reduce channel inactivation; resulting in excess Ca2+ entry during the action potential, calcium channel blockers (CCBs) would seem to represent a promising treatment option. Yet CCBs have been unsuccessful in the treatment of LQT8. Here, we demonstrate that this lack of efficacy likely stems from the impact of the mutations on CaV1.2 channel inactivation. As CCBs are known to preferentially bind to the inactivated state of the channel, mutation-dependent deficits in inactivation result in a decrease in use-dependent block of the mutant channel. Further, application of the CCB verapamil to induced pluripotent stem cell (iPSC) derived cardiomyocytes from an LQT8 patient demonstrates that this loss of use-dependent block translates to a lack of efficacy in correcting the LQT phenotype. As a growing number of channelopathic mutations demonstrate effects on channel inactivation, reliance on state-dependent blockers may leave a growing population of patients without a viable treatment option. This biophysical understanding of the interplay between inactivation deficits and state-dependent block may provide a new avenue to guide the development of improved therapies.
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与长QT综合征相关的钙调蛋白突变可防止心脏L型Ca（2+）电流失活，并促进心室心肌细胞中心律失常。
影响因子：
5
作者：
Limpitikul, Worawan B.;Dick, Ivy E.;Joshi-Mukherjee, Rosy;Overgaard, Michael T.;George, Alfred L., Jr.;Yue, David T.
通讯作者：
Yue, David T.
影响因子：
11
作者：
Gershon, E. S.;Grennan, K.;Busnello, J.;Badner, J. A.;Ovsiew, F.;Memon, S.;Alliey-Rodriguez, N.;Cooper, J.;Romanos, B.;Liu, C.
通讯作者：
Liu, C.
DOI：
10.1111/j.1524-6175.2004.03683.x
发表时间：
2004-11-01
期刊：
Journal of clinical hypertension (Greenwich, Conn.)
影响因子：
--
作者：
Basile, Jan
通讯作者：
Basile, Jan
影响因子：
5.5
作者：
Brody, DL;Patil, PG;Yue, DT
通讯作者：
Yue, DT
DOI：
10.1196/annals.1341.008
发表时间：
2005-01-01
期刊：
COMMUNICATIVE CARDIAC CELL
影响因子：
--
作者：
Bers, DM;Guo, T
通讯作者：
Guo, T