@article {Wang525, author = {Lu Wang and Barbara A. Wible and Xiaoping Wan and Eckhard Ficker}, title = {Cardiac Glycosides as Novel Inhibitors of Human Ether-a-go-go-Related Gene Channel Trafficking}, volume = {320}, number = {2}, pages = {525--534}, year = {2007}, doi = {10.1124/jpet.106.113043}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na+/K+ pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K+ current (IKr) currents by approximately 50\%, whereas three other cardiac membrane currents{\textemdash}inward rectifier current, slowly activating delayed rectifier K+ current, and calcium current{\textemdash}were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/IKr channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/320/2/525}, eprint = {https://jpet.aspetjournals.org/content/320/2/525.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }