hERG基因变异与全麻药物致QT间期延长的遗传易感性及分子机制

In recent years，drug-induced acquired long QT syndrome (LQTS) is widely observed, which became the potential risk of anesthesia. More and more evidences demonstrated that subclinical hereditary LQTS caused by gene mutation is an important risk factor for drug-induced LQTS，however, the genetic susceptibility mechanism of anesthesia drugs-induced LQTS is not clear. Our previous studies have confirmed that propofol is approximately 4-fold more potent in inhibiting WT/Q738X-hERG than WT-hERG currents.Therefore, we hypothesized that general anesthesia increase the inhibition capacity of hERG channel caused by hERG gene mutation. Our group will study: 1）the molecular mechanism of hERG potassium channel inhibited by anesthesia drugs (propofol, ketamine, midazolam and thiopental); 2）the functional identification of hERG gene mutant (A614V and Q738X); 3）the susceptibility of anesthesia drugs-induced LQTS associated with gene mutation. The study will shed light on the genetic susceptibility mechanism of anesthesia drugs-induced LQTS associated with hERG gene variants, and will provide theoretical basis for the clinical individual administration.

近年来由于药物所引起的获得性长QT综合征（LQTS）更为常见，成为手术麻醉的潜在风险。而且越来越多的证据表明，基因突变所致亚临床遗传性LQTS是药源性LQTS的重要危险因素之一，但与全麻药物致LQTS的遗传易感性机制尚不清楚。我们前期工作证实：hERG基因变异（WT/Q738X-hERG）时，丙泊酚抑制hERG钾通道的能力增加约4倍。由此提出假说：hERG基因变异增加全麻药物抑制hERG钾通道的易感性，使发生药源性LQTS的风险增加。本课题组拟研究：1）全麻药物（以丙泊酚、氯胺酮、咪达唑仑和硫喷妥钠为代表）抑制hERG钾通道的分子机制；2）hERG基因变异（A614V和Q738X）的功能鉴定；3）hERG基因变异与全麻药物致LQTS的易感性。该研究阐明hERG基因变异与全麻药物致LQTS的遗传易感性的分子机制，将为临床个体化给药提供理论依据。

由于药物引起的获得性长QT综合征（LQTS）在临床上较常见，成为手术麻醉的潜在风险。而且越来越多的证据表明，基因突变所致亚临床遗传性LQTS是药源性LQTS的重要危险因素之一，但与全麻药物致LQTS的遗传易感性机制尚不清楚。本课题组研究内容有：1. hERG基因变异（Q738X）的功能鉴定；2. 阿扎那韦抑制hERG钾通道的分子机制；3. 全麻药物及其相关药物（以丙泊酚、咪达唑仑和依托咪酯）抑制hERG钾通道的分子机制；4. hERG基因变异与全麻药物（丙泊酚）致LQTS的易感性。实验结果如下：1. 突变体Q738X可导致hERG蛋白功能的丧失，对野生型WT-hERG钾通道无负显性抑制，其运输障碍是由于不能形成有功能的四聚体所致；2. 阿扎那韦能够通过阻断Y652和H656位点抑制hERG钾通道，并且阻碍hERG蛋白的膜运输。3.咪达唑仑能阻断hERG钾通道，失活速度加快，Y652和F656可能是咪达唑仑与hERG钾通道结合的关键位点；4. 依托咪酯呈浓度依赖性抑制HEK-293细胞上hERG钾通道电流，对激活曲线和失活曲线无显著影响。F656C是依托咪酯与hERG钾通道相互作用的重要靶点。5. 丙泊酚可直接抑制WT-hERG电流，具有浓度依赖性和时间依赖性，而无频率依赖性，对其动力学特征（激活、失活和去活）无明显影响；丙泊酚与位点Y652和F656有高亲和力；丙泊酚对WT-hERG蛋白的运输无影响； 与抑制野生型hERG钾通道相比，丙泊酚抑制WT/Q738X-hERG, WT/A422T-hERG and WT/H562P-hERG的能力分别增加了4，18,10倍。由此得出结论：hERG基因变异增加全麻药物抑制hERG钾通道的易感性，使发生药源性LQTS的风险增加。该研究阐明hERG基因变异与全麻药物及其相关药物致LQTS的遗传易感性的分子机制，将为临床个体化给药提供理论依据。