IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines
IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines
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DOI：
10.1096/fj.02-1057fje
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发表时间：
2003-10-01
期刊：
影响因子：
4.8
通讯作者：
Balser, JR
中科院分区：
文献类型：
--
作者：
Kupershmidt, S;Yang, ICH;Balser, JR
由人类ether-a-go-go相关基因（HERG）编码的心脏钾通道可被多种常见治疗化合物阻断。即使短暂暴露于这些药物也可能在一些但不是所有个体中引起危及生命的心律失常尖端扭转型室性心动过速。尽管预测药物反应如此广泛变异性的分子和遗传因素尚不清楚，但HERG编码区内的已知序列变异在许多情况下不能解释药物不良反应。虽然其他蛋白质可以调节HERG功能，但没有研究确定能够限制HERG药理学敏感性的蛋白质伴侣。在这里，我们表明，KCR 1，以前在大鼠小脑中发现的蛋白质，是一种质膜相关蛋白在RNA水平上表达在人类心脏，可以与HERG免疫沉淀。在功能上，KCR 1可降低心脏和非心脏细胞系中HERG对经典促肾上腺皮质激素HERG阻断剂（索他洛尔、奎尼丁、多非利特）的敏感性。我们建议，KCR 1，当耦合到HERG，可能会限制HERG的敏感性，以promammic药物封锁，并可能是一个合理的目标，修改promammic的效果，否则临床上有用的化合物。
The cardiac potassium channel encoded by the human ether-a-go-go related gene (HERG) is blocked by a diverse array of common therapeutic compounds. Even transient exposure to such agents may provoke the life-threatening cardiac arrhythmia torsades de pointes in some, but not all, individuals. Although the molecular and genetic factors predicting such wide variability in drug response remain unclear, known sequence variations within the coding region of HERG do not explain the adverse drug response in many cases. Although other proteins can modulate HERG function, no studies have identified protein partners capable of limiting the pharmacological sensitivity of HERG. Here we show that KCR1, a protein identified previously in rat cerebellum, is a plasma membrane-associated protein expressed at the RNA level in the human heart and can be immunoprecipitated with HERG. Functionally, KCR1 reduces the sensitivity of HERG to classic proarrhythmic HERG blockers (sotalol, quinidine, dofetilide) in both cardiac and noncardiac cell lines. We propose that KCR1, when coupled to HERG, may limit the sensitivity of HERG to proarrhythmic drug blockade and may be a rational target for modifying the proarrhythmic effects of otherwise clinically useful compounds.