Received for publication August 30, 2006.
Revised November 8, 2006.
Accepted for publication November 8, 2006.

Cardiac Glycosides as Novel Inhibitors of HERG Channel Trafficking

Abstract

Direct block of the cardiac potassium channel 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. Similarly, 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/I_Kr currents by about 50% while three other cardiac membrane currents, I_K1, I_Ks and I_Ca were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I_Kr 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.

Key words: HERG, KCNH2, arrhythmia, cardiac glycosides, ion channel trafficking, potassium channel

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