Zf. Zhou et al., Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome - Pharmacological and temperature effects, J BIOL CHEM, 274(44), 1999, pp. 31123-31126
The chromosome 7-linked form of congenital long QT syndrome (LQT2) is cause
d by mutations in the human ether-a-go-go-related gene (HERG) that encodes
the rapidly activating delayed rectifier potassium channel. One mechanism f
or the loss of normal channel function in LQT2 is defective protein traffic
king, which results in the failure of the channel protein to reach the plas
ma 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 de
grees C its trafficking to the plasma membrane and channel function are mar
kedly improved. We further show that the antiarrhythmic drug E-4031, which
selectively blocks HERO channels, also corrects defective protein trafficki
ng of the N470D mutant and can restore the generation of HERO current. Simi
lar findings were obtained with the drugs astemizole and cisapride, as well
as with high concentrations of glycerol. The effect of E-4031 on HERO prot
ein trafficking was concentration-dependent and required low drug concentra
tions (saturation present at 5 mu M), developed rapidly with drug exposure,
and occurred post-translationally. These findings suggest that protein misf
olding leading to defective trafficking of some HERO LQT mutations may be c
orrected by specific pharmacological strategies.