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.