Pharmacological rescue of specific long QT variants of KCNQ1/KCNE1 channels.
Pharmacological rescue of specific long QT variants of KCNQ1/KCNE1 channels.
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DOI：
10.3389/fphys.2022.902224
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发表时间：
2022
影响因子：
4
通讯作者：
Kass, Robert S.
中科院分区：
文献类型：
--
作者：
Zou, Xinle;Wu, Xiaoan;Sampson, Kevin J.;Colecraft, Henry M.;Larsson, H. Peter;Kass, Robert S.
先天性长QT综合征（LQTS）是一种遗传性疾病，其中心室复极延迟并使患者易于心律失常和心源性猝死。LQT 1和LQT 5分别是由KCNQ 1或KCNE 1基因突变引起的LQTS变体。KCNQ 1和KCNE 1共同组装形成关键的IKS钾通道。β受体阻滞剂是治疗LQT 1的标准治疗，然而，这样做是基于纠正K+通道功能丧失以外的机制。ML 277和R-L3是以依赖于组装通道中KCNE 1亚基的化学计量的方式增强IKS通道和减缓通道失活的化合物。在本文中，我们使用IKS通道在中国仓鼠卵巢（CHO）细胞和爪蟾卵母细胞中的表达来研究这两种药物（ML 277和R-L3）拯救LQT 1和LQT 5突变通道的潜力。我们重点研究了LQT 1突变KCNQ 1-S546 L和两个LQT 5突变KCNE 1-L51 H和KCNE 1-G52 R。我们发现ML 277和R-L3增强了IKS复合体-KCNE 1-G52 R和KCNE 1-L51 H以及模拟患者突变异质表达的异质IKS通道复合体中的纯合子LQTS突变。ML 277和R-L3增加突变体IKS电流幅度并减缓电流失活，但在野生型（WT）IKS中不增加。我们用ML 277和R-L3在LQT 1突变体（KCNQ 1 S546 L/KCNE 1）中获得了类似的结果。ML 277和R-L3对LQT 1和LQT 5突变体具有相似的作用，然而，ML 277在这种调节中比R-L3更有效。重要的是，我们发现并非所有与KCNQ 1一起表达的LQT 5突变体都导致这些药物增强的通道，因为KCNE 1突变体D 76 N在与KCNQ 1一起表达时抑制药物作用。因此，我们的工作表明，通过直接研究ML 277和R-L3对LQT 1和LQT 5突变的治疗，我们将了解这些激活剂作为特定LQTS治疗方案的潜在效用。
The congenital Long QT Syndrome (LQTS) is an inherited disorder in which cardiac ventricular repolarization is delayed and predisposes patients to cardiac arrhythmias and sudden cardiac death. LQT1 and LQT5 are LQTS variants caused by mutations in KCNQ1 or KCNE1 genes respectively. KCNQ1 and KCNE1 co-assemble to form critical IKS potassium channels. Beta-blockers are the standard of care for the treatment of LQT1, however, doing so based on mechanisms other than correcting the loss-of-function of K+ channels. ML277 and R-L3 are compounds that enhance IKS channels and slow channel deactivation in a manner that is dependent on the stoichiometry of KCNE1 subunits in the assembled channels. In this paper, we used expression of IKS channels in Chinese hamster ovary (CHO) cells and Xenopus oocytes to study the potential of these two drugs (ML277 and R-L3) for the rescue of LQT1 and LQT5 mutant channels. We focused on the LQT1 mutation KCNQ1-S546L, and two LQT5 mutations, KCNE1-L51H and KCNE1-G52R. We found ML277 and R-L3 potentiated homozygote LQTS mutations in the IKS complexes-KCNE1-G52R and KCNE1-L51H and in heterogeneous IKS channel complexes which mimic heterogeneous expression of mutations in patients. ML277 and R-L3 increased the mutant IKS current amplitude and slowed current deactivation, but not in wild type (WT) IKS. We obtained similar results in the LQT1 mutant (KCNQ1 S546L/KCNE1) with ML277 and R-L3. ML277 and R-L3 had a similar effect on the LQT1 and LQT5 mutants, however, ML277 was more effective than R-L3 in this modulation. Importantly we found that not all LQT5 mutants expressed with KCNQ1 resulted in channels that are potentiated by these drugs as the KCNE1 mutant D76N inhibited drug action when expressed with KCNQ1. Thus, our work shows that by directly studying the treatment of LQT1 and LQT5 mutations with ML277 and R-L3, we will understand the potential utility of these activators as options in specific LQTS therapeutics.
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转诊进行 FAMILION 长 QT 综合征基因检测的前 2,500 名连续无关患者的突变谱和患病率。
影响因子：
5.5
作者：
Kapplinger, Jamie D.;Tester, David J.;Salisbury, Benjamin A.;Carr, Janet L.;Harris-Kerr, Carole;Pollevick, Guido D.;Wilde, Arthur A. M.;Ackerman, Michael J.
通讯作者：
Ackerman, Michael J.
DOI：
10.1152/ajpheart.2000.279.6.h3003
发表时间：
2000-12-01
影响因子：
4.8
作者：
Bianchi, L;Priori, SG;Brown, AM
通讯作者：
Brown, AM
影响因子：
4
作者：
Dvir, Meidan;Peretz, Asher;Attali, Bernard
通讯作者：
Attali, Bernard
DOI：
10.1085/jgp.116.3.379
发表时间：
2000-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Tapper AR;George AL Jr
通讯作者：
George AL Jr
影响因子：
64.8
作者：
Sanguinetti, MC;Curran, ME;Keating, MT
通讯作者：
Keating, MT