Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing.
Human hereditary long QT syndrome is a cardiac disease characterized by prolongation of the QT interval and increased susceptibility to ventricular arrhythmias and sudden cardiac death. Mutations in the human-ether-a-go-go-related gene (hERG), encoding the protein underlying the repolarizing cardiac I(Kr) potassium current, cause chromosome 7-linked long QT syndrome 2. Loss of function of mutant hERG channels may be caused by several mechanisms, including altered current kinetics, altered ion selectivity, or defective intracellular protein trafficking. Especially the latter category has become a focus of particular interest recently, because some of the mutant subunits display wild type current properties when normal trafficking is restored and channels are inserted in the cell membrane in vitro. This review summarizes the current knowledge on hERG channel trafficking under physiological and pathological conditions. In addition, therapeutic approaches to restore normal hERG trafficking in vitro and in vivo are discussed.
Thomas
Dierk
D
Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, D-69115 Heidelberg, Germany. dierk_thomas@med.uni-heidelberg.de
Kiehn
Johann
J
Katus
Hugo A
HA
Karle
Christoph A
CA
D000818:Animals; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D008133:Long QT Syndrome / Q000188:drug therapy / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
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; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG