Mechanisms underlying probucol-induced hERG-channel deficiency.
Mechanisms underlying probucol-induced hERG-channel deficiency.
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普罗布考诱导 hERG 通道缺陷的机制
DOI：
10.2147/dddt.s86724
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Li BX
中科院分区：
文献类型：
--
作者：
Shi YQ;Yan CC;Zhang X;Yan M;Liu LR;Geng HZ;Lv L;Li BX
hERG基因编码快速激活延迟整流钾通道（IKr）的成孔α亚基，这对心脏复极非常重要。由于基因突变或药物干扰导致的IhERG降低可引起长QT综合征，从而导致危及生命的心律失常（尖端扭转型室性心动过速）或猝死。普罗布考是一种降胆固醇药物，可通过降低细胞膜hERG蛋白表达而降低hERG电流，最终导致长QT综合征。在这里，我们研究了普罗布考对IhERG和hERG通道表达的影响机制。我们的数据表明，普罗布考降低SGK 1的表达，称为SGK亚型，在浓度依赖性的方式，导致下调磷酸化E3泛素连接酶Nedd 4 -2的表达，但不是Nedd 4 -2的总水平。结果，由于增强的泛素化水平，hERG蛋白减少。相反，卡巴胆碱可增强Nedd 4 -2的磷酸化水平，从而改善probucol引起的泛素介导的hERG通道降解。这些发现提供了普罗布考诱导的hERG通道缺陷的新机制，并暗示卡巴胆碱或其类似物可作为处理普罗布考心脏毒性的潜在治疗化合物。
The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Reduction of IhERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes) or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on IhERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.