hERG channel trafficking: novel targets in drug-induced long QT syndrome.
The cardiac potassium channel hERG (human ether-a-go-go-related gene) encodes the alpha-subunit of the rapid delayed rectifier current I(Kr) in the heart, which contributes to terminal repolarization in human cardiomyocytes. Direct block of hERG/I(Kr) channels by a large number of therapeutic compounds produces acLQTS [acquired LQTS (long QT syndrome)] characterized by drug-induced QT prolongation and torsades de pointes arrhythmias. The cardiotoxicity associated with unintended hERG block has prompted pharmaceutical companies to screen developmental compounds for hERG blockade and made hERG a major target in drug safety programmes. More recently, a novel form of acLQTS has been discovered that may go undetected in most conventional safety assays. Several therapeutic compounds have been identified that reduce hERG/I(Kr) currents not by direct block but by inhibition of hERG/I(Kr) trafficking to the cell surface. Important examples are antineoplastic Hsp90 (heat-shock protein 90) inhibitors such as (i) geldanamycin, (ii) the leukaemia drug arsenic trioxide, (iii) the antiprotozoical pentamidine, (iv) probucol, a cholesterol-lowering drug, and (v) fluoxetine, a widely used antidepressant. Increased awareness of drug-induced hERG trafficking defects will help to further reduce the potentially lethal adverse cardiac events associated with acLQTS.
Dennis
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A
Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109, U.S.A.
Wang
L
L
Wan
X
X
Ficker
E
E
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000378:metabolism*; D021381:Protein Transport
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018841:HSP90 Heat-Shock Proteins; C000606913:KCNH2 protein, human