Intracellular potassium stabilizes human ether-à-go-go-related gene channels for export from endoplasmic reticulum.
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.
Wang
Lu
L
Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109, USA.
Dennis
Adrienne T
AT
Trieu
Phan
P
Charron
Francois
F
Ethier
Natalie
N
Hebert
Terence E
TE
Wan
Xiaoping
X
Ficker
Eckhard
E
D002301:Cardiac Glycosides / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology
D002301:Cardiac Glycosides; D051638:Ether-A-Go-Go Potassium Channels; D011188:Potassium