HERG is protected from pharmacological block by α-1,2-glucosyltransferase function
HERG is protected from pharmacological block by α-1,2-glucosyltransferase function
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DOI：
10.1074/jbc.m605976200
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发表时间：
2007-02-23
影响因子：
4.8
通讯作者：
Kupershmidt, Sabina
中科院分区：
文献类型：
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作者：
Nakajima, Tadashi;Hayashi, Kenshi;Kupershmidt, Sabina
HERG（人类ether-A-go-go-related基因）蛋白是心脏复极化电流I-Kr的基础，是许多药物的非预期靶点。IKr的意外阻断，称为获得性长QT综合征（aLQTS），是美国食品和药物管理局停药的主要原因。因此，更好地了解保护大多数人免受aLQTS的调节因素对于推进从癌症化疗到抗精神病药和抗抑郁药等广泛领域的临床治疗至关重要。在这里，我们表明，K+通道调节蛋白KCR 1，显着降低I，，药物敏感性，保护HERG通过葡糖基转移酶功能。KCR 1和酵母α-1，2-葡糖基转移酶ALG 10显示出序列同源性，并且与KCR 1一样，ALG 10减少了多非利特对HERG的阻断。用衣霉素抑制细胞糖基化途径消除了KCR 1的作用，Lec 1细胞（糖基化缺陷）中的表达也是如此。此外，KCR 1补充了alg 10缺陷型酵母菌株的生长缺陷，并增强了酵母中Alg 10底物的糖基化。HERG本身不是KCR 1介导的糖基化的靶点，因为糖基化缺陷型HERG（N598 Q）的多非利特反应仍受KCR 1调节。尽管如此，我们的数据表明，α-1，2-葡糖基转移酶的功能是一个关键组成部分的分子途径，从而KCR 1减少I，药物反应。将体外数据纳入计算模型表明，KCR 1表达对心律失常具有保护作用。这些发现揭示了一个潜在的新途径，有针对性地预防aLQTS。
The HERG (human ether-A-go-go-related gene) protein, which underlies the cardiac repolarizing current I-Kr is the unintended target for many pharmaceutical agents. Inadvertent block Of IKr, known as the acquired long QT syndrome (aLQTS), is a leading cause for drug withdrawal by the United States Food and Drug Administration. Hence, an improved understanding of the regulatory factors that protect most individuals from aLQTS is essential for advancing clinical therapeutics in broad areas, from cancer chemotherapy to antipsychotics and antidepressants. Here, we show that the K+ channel regulatory protein KCR1, which markedly reduces I,,, drug sensitivity, protects HERG through glucosyltransferase function. KCR1 and the yeast alpha-1,2-glucosyltransferaseALG10 exhibit sequence homology, and like KCR1, ALG10 diminished HERG block by dofetilide. Inhibition of cellular glycosylation pathways with tunicamycin abrogated the effects of KCR1 as did expression in Lec1 cells (deficient in glycosylation). Moreover, KCR1 complemented the growth defect of an alg10-deficient yeast strain and enhanced glycosylation of an Alg10 substrate in yeast. HERG itself is not the target for KCR1-mediated glycosylation because the dofetilide response of glycosylation-deficient HERG(N598Q) was still modulated by KCR1. Nonetheless, our data indicate that the alpha-1,2-glucosyltransferase function is a key component of the molecular pathway whereby KCR1 diminishes I,, drug response. Incorporation of in vitro data into a computational model indicated that KCR1 expression is protective against arrhythmias. These findings reveal a potential new avenue for targeted prevention of aLQTS.