RT Journal Article SR Electronic T1 Intracellular Potassium Stabilizes Human Ether-à-go-go-Related Gene Channels for Export from Endoplasmic Reticulum JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 927 OP 937 DO 10.1124/mol.108.053793 VO 75 IS 4 A1 Lu Wang A1 Adrienne T. Dennis A1 Phan Trieu A1 Francois Charron A1 Natalie Ethier A1 Terence E. Hebert A1 Xiaoping Wan A1 Eckhard Ficker YR 2009 UL http://molpharm.aspetjournals.org/content/75/4/927.abstract AB Several therapeutic compounds have been identified that prolong the QT interval on the electrocardiogram and cause torsade de pointes arrhythmias not by direct block of the cardiac potassium channel human ether-à-go-go-related gene (hERG) but via disruption of hERG trafficking to the cell surface membrane. One example of a clinically important compound class that potently inhibits hERG trafficking are cardiac glycosides. We have shown previously that inhibition of hERG trafficking by cardiac glycosides is initiated via direct block of Na+/K+ pumps and not via off-target interactions with hERG or any other protein. However, it was not known how pump inhibition at the cell surface is coupled to hERG processing in the endoplasmic reticulum. Here, we show that depletion of intracellular K+—either indirectly after long-term exposure to cardiac glycosides or directly after exposure to gramicidin in low sodium media—is sufficient to disrupt hERG trafficking. In K+-depleted cells, hERG trafficking can be restored by permeating K+ or Rb+ ions, incubation at low temperature, exposure to the pharmacological chaperone astemizole, or specific mutations in the selectivity filter of hERG. Our data suggest a novel mechanism for drug-induced trafficking inhibition in which cardiac glycosides produce a [K+]i-mediated conformational defect directly in the hERG channel protein. The American Society for Pharmacology and Experimental Therapeutics