Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes.
Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes.
复制标题
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。
DOI：
10.1016/j.yjmcc.2014.04.022
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发表时间：
2014-09
影响因子：
5
通讯作者：
Yue, David T.
中科院分区：
文献类型：
--
作者：
Limpitikul, Worawan B.;Dick, Ivy E.;Joshi-Mukherjee, Rosy;Overgaard, Michael T.;George, Alfred L., Jr.;Yue, David T.
关键词：
最近的研究发现钙调蛋白 (CaM) 中的错义突变与严重的早发性长 QT 综合征 (LQTS) 相关，从而提出 CaM 功能改变可能有助于该 LQTS 子集的分子病因学的主张。然而，迄今为止，还没有实验证据证明这些突变是 LQTS 底物的直接原因，也没有确定 CaM 突变体的分子靶标。因此，我们在这里测试成年豚鼠心室肌细胞 (aGPVM) 中 CaM 突变体的表达是否会诱导动作电位延长，以及 L 型 Ca2+ 通道 (LTCC) 的 Ca2+ 调节的相关改变是否可能导致这种延长。特别是，我们首先在 aGPVM 中过表达 CaM 突变体，并观察到动作电位持续时间 (APD) 增加和 Ca2+ 瞬变增加。接下来，我们证明所有 LQTS CaM 突变体都有可能强烈抑制 LTCC 的 Ca2+/CaM 依赖性失活 (CDI)，无论通道是在 HEK293 细胞中异源表达，还是以天然形式存在于肌细胞内。预计 CDI 的减弱会促进动作电位延长并促进 Ca2+ 流入。最后，我们证明了一小部分 LQTS CaM 突变体（如杂合子患者）如何足以大幅减少 CDI，并扰乱电和 Ca2+ 分布。总之，这些结果强调了 LTCC 作为理解和治疗该组患者中 CaM 相关 LQTS 的分子位点。
Recent work has identified missense mutations in calmodulin (CaM) that are associated with severe early-onset long-QT syndrome (LQTS), leading to the proposition that altered CaM function may contribute to the molecular etiology of this subset of LQTS. To date, however, no experimental evidence has established these mutations as directly causative of LQTS substrates, nor have the molecular targets of CaM mutants been identified. Here, therefore, we test whether expression of CaM mutants in adult guinea-pig ventricular myocytes (aGPVM) induces action-potential prolongation, and whether affiliated alterations in the Ca2+ regulation of L-type Ca2+ channels (LTCC) might contribute to such prolongation. In particular, we first overexpressed CaM mutants in aGPVMs, and observed both increased action potential duration (APD) and heightened Ca2+ transients. Next, we demonstrated that all LQTS CaM mutants have the potential to strongly suppress Ca2+/CaM-dependent inactivation (CDI) of LTCCs, whether channels were heterologously expressed in HEK293 cells, or present in native form within myocytes. This attenuation of CDI is predicted to promote action-potential prolongation and boost Ca2+ influx. Finally, we demonstrated how a small fraction of LQTS CaM mutants (as in heterozygous patients) would nonetheless suffice to substantially diminish CDI, and derange electrical and Ca2+ profiles. In all, these results highlight LTCCs as a molecular locus for understanding and treating CaM-related LQTS in this group of patients.
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DOI：
10.1073/pnas.262372999
发表时间：
2002-12-24
影响因子：
11.1
作者：
Alseikhan, BA;DeMaria, CD;Yue, DT
通讯作者：
Yue, DT
影响因子：
5
作者：
Joshi-Mukherjee, Rosy;Dick, Ivy E.;Liu, Ting;O'Rourke, Brian;Yue, David T.;Tung, Leslie
通讯作者：
Tung, Leslie
影响因子：
16.2
作者：
Erickson, MG;Alseikhan, BA;Yue, DT
通讯作者：
Yue, DT
影响因子：
64.8
作者：
Dick, Ivy E.;Tadross, Michael R.;Yue, David T.
通讯作者：
Yue, David T.
影响因子：
4.5
作者：
Busch, AE;Suessbrich, H;Maylie, JG
通讯作者：
Maylie, JG