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 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.
Zhou
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Section of Cardiology, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
Gong
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January
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D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016589:Astemizole / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D027682:Cation Transport Proteins; D002451:Cell Compartmentation; D020117:Cisapride / Q000494:pharmacology; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005990:Glycerol / Q000494:pharmacology; D006801:Humans; D008133:Long QT Syndrome / Q000151:congenital* / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D017510:Protein Folding; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000187:drug effects; D013696:Temperature; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D011994:Recombinant Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C063968:E 4031; D016589:Astemizole; D005990:Glycerol; D020117:Cisapride