Ficker Eckhard, Dennis Adrienne, Kuryshev Yuri, Wible Barbara A, Brown Arthur M
Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland OH 44109, USA.
Novartis Found Symp. 2005;266:57-69; discussion 70-4, 95-9.
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.
心脏钾通道hERG/IKr的突变会导致遗传性长QT综合征，增加室性心律失常的易感性。hERG中的几种突变会产生滞留在内质网（ER）中的运输缺陷型通道。某些突变（如hERG G601S）的表面表达可通过特定的通道阻滞剂恢复。尽管对hERG电流进行了广泛研究，但对加工途径中的蛋白质了解甚少。我们通过生化和电生理分析表明，胞质伴侣蛋白Hsp70和Hsp90与野生型hERG短暂相互作用。抑制Hsp90会阻止成熟并降低hERG/IKr电流。运输缺陷型突变体在内质网中与伴侣蛋白紧密结合，直到运输恢复，例如通过通道阻滞剂。hERG/伴侣蛋白复合物是具有心脏毒性的治疗化合物（如用于治疗白血病的砷）的新靶点。砷会干扰hERG/伴侣蛋白复合物的形成并抑制hERG成熟，导致心电图异常。我们得出结论，Hsp90和Hsp70对野生型hERG的有效折叠至关重要。抑制伴侣蛋白功能的治疗化合物会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滞，而是通过hERG获得性运输缺陷导致表面表达降低。
