Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome - Pharmacological and temperature effects

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.