Pharmacological rescue of human K+ channel long-QT2 mutations -: Human ether-a-go-go-related gene rescue without block
Pharmacological rescue of human K+ channel long-QT2 mutations -: Human ether-a-go-go-related gene rescue without block
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DOI：
10.1161/01.cir.0000019513.50928.74
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发表时间：
2002-06-18
期刊：
影响因子：
37.8
通讯作者：
January, CT
中科院分区：
文献类型：
--
作者：
Rajamani, S;Anderson, C;January, CT
背景：蛋白质运输缺陷是基因突变的结果。人类长qt （LQT）综合征是由几个基因突变引起的，包括人类以太相关基因（HERG），该基因编码延迟整流K+电流。转运缺陷突变的HERG蛋白是LQT2中延迟整流K+电流减少的机制，高亲和力的HERG通道阻断药物可导致药物救援。方法和结果-我们假设经过修饰去除高亲和力HERG块的药物分子仍然可以将突变蛋白稳定在救援所需的构象中。我们测试了羧酸特非那定（非索非那定）和特非那定这两种结构相似但对HERG阻滞的亲和力明显不同的药物对转运缺陷LQT2突变的拯救作用。特非那定挽救了N470D突变，但阻断了通道。非索非那定对N470D的半最大拯救浓度为177 nmol/L，比半最大通道阻断浓度低约350倍。G601S突变也在没有通道阻滞的情况下获救。结论：药物救援可在无通道阻滞的情况下发生。这可能代表了治疗一些运输缺陷LQT2突变的一种新的抗心律失常范例。
Background-Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K+ current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K+ current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue.Methods and Results-We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is approximate to350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block.Conclusions-Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.