The chromosome 7-linked form of congenital long QT syndrome (LQT2) is caused by 
mutations in the human ether-a-go-go-related gene (HERG) that encodes the 
rapidly activating delayed rectifier potassium channel. One mechanism for the 
loss of normal channel function in LQT2 is defective protein trafficking, which 
results in the failure of the channel protein to reach the plasma membrane. Here 
we show that the N470D LQT2 mutant protein is trafficking-deficient when 
expressed at 37 degrees C in HEK293 cells, whereas at 27 degrees C its 
trafficking to the plasma membrane and channel function are markedly improved. 
We further show that the antiarrhythmic drug E-4031, which selectively blocks 
HERG channels, also corrects defective protein trafficking of the N470D mutant 
and can restore the generation of HERG current. Similar findings were obtained 
with the drugs astemizole and cisapride, as well as with high concentrations of 
glycerol. The effect of E-4031 on HERG protein trafficking was 
concentration-dependent and required low drug concentrations (saturation present 
at 5 microM), developed rapidly with drug exposure, and occurred 
post-translationally. These findings suggest that protein misfolding leading to 
defective trafficking of some HERG LQT mutations may be corrected by specific 
pharmacological strategies.