HERG channel trafficking.
HERG channel trafficking.
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DOI：
10.1002/047002142x.ch6
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发表时间：
2005
影响因子：
--
通讯作者：
E. Ficker;A. Dennis;Y. Kuryshev;B. Wible;A. Brown
中科院分区：
文献类型：
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作者：
E. Ficker;A. Dennis;Y. Kuryshev;B. Wible;A. Brown
心脏钾通道hERG/IKr突变导致遗传性长QT综合征，并增加室性心律失常的易感性。hERG的一些突变会产生保留在内质网（ER）中的运输缺陷通道。特定的通道阻滞剂可以恢复某些突变（如hERG G601S）的表面表达。虽然hERG电流已被广泛研究，但对加工途径中的蛋白质知之甚少。通过生化和电生理实验，我们发现细胞质伴侣蛋白Hsp70和Hsp90与野生型hERG有短暂的相互作用。抑制Hsp90可阻止成熟并降低hERG/IKr电流。缺乏贩运的突变体与内质网中的伴侣蛋白保持紧密联系，直到贩运恢复，例如通过通道阻滞剂。hERG/伴侣复合物代表了具有心脏倾向性的治疗性化合物的新靶点，例如用于治疗白血病的砷。砷干扰hERG/伴侣复合物的形成，抑制hERG成熟，导致ECG异常。我们得出结论，hsp90和Hsp70对野生型hERG的高产折叠至关重要。抑制伴侣蛋白功能的治疗性化合物产生一种新形式的获得性长QT综合征，不是通过直接通道阻断，而是通过获得性hERG转运缺陷导致的表面表达减少。
Mutations in the cardiac potassium channel hERG/IKr cause inherited long QT syndrome with increased susceptibility to ventricular arrhythmias. Several mutations in hERG produce trafficking-deficient channels that are retained in the endoplasmic reticulum (ER). Surface expression of certain mutations (i.e. hERG G601S) can be restored by specific channel blockers. Although hERG currents have been studied extensively, little is known about proteins in the processing pathway. Using biochemical and electrophysiological assays we show that the cytosolic chaperones Hsp70 and Hsp90 interact transiently with wild-type hERG. Inhibition of Hsp90 prevents maturation and reduces hERG/IKr currents. Trafficking-deficient mutants remain tightly associated with chaperones in the ER until trafficking is restored, e.g. by channel blockers. hERG/chaperone complexes represent novel targets for therapeutic compounds with cardiac liability such as arsenic, which is used in the treatment of leukaemias. Arsenic interferes with the formation of hERG/chaperone complexes and inhibits hERG maturation causing ECG abnormalities. We conclude that Hsp9O and Hsp70 are crucial for productive folding of wild-type hERG. Therapeutic compounds that inhibit chaperone function produce a novel form of acquired long QT syndrome not by direct channel block but by reduced surface expression due to an acquired trafficking defect of hERG.