4.5 Article

Impaired CaV1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8

期刊

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2022.10.003

关键词

Long -QT syndrome; Voltage -gated calcium channel; Ion channel; Channelopathy

资金

  1. NIH/NHLBI [1R01HL149926]
  2. Maryland Stem Cell Research Fund [MSCRF-3688]
  3. AHA postdoctoral fellowship [20POST35211127]

向作者/读者索取更多资源

Mutations in the CaV1.2 L-type calcium channel can cause longQT type 8 (LQT8), leading to fatal cardiac arrhythmias. Current therapies with calcium channel blockers (CCBs) are unsuccessful due to mutation-induced deficits in channel inactivation, resulting in decreased use-dependent block of the mutant channel. Understanding the interplay between inactivation deficits and state-dependent block may guide the development of improved therapies for channelopathic mutations.
Mutations in the CaV1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as longQT 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.5
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据