title: Identification of a COOH-terminal segment involved in maturation and stability of human ether-a-go-go-related gene potassium channels.
abstract: Mutations in the potassium channel encoded by the human ether-a-go-go-related gene (HERG) have been linked to the congenital long QT syndrome (LQTS), a cardiac disease associated with an increased preponderance of ventricular arrhythmias and sudden death. The COOH terminus of HERG harbors a large number of LQTS mutations and its removal prevents functional expression for reasons that remain unknown. In this study, we show that the COOH terminus of HERG is required for normal trafficking of the ion channel. We have identified a region critical for trafficking between residues 860 and 899 that includes a novel missense mutation at amino acid 861 (HERGN861I). Truncations or deletion of residues 860-899, characterized in six different expression systems including a cardiac cell line, resulted in decreased expression levels and an absence of the mature glycosylated form of the HERG protein. Deletion of this region did not interfere with the formation of tetramers but caused retention of the assembled ion channels within the endoplasmic reticulum. Consequently, removal of residues 860-899 resulted in the absence of the ion channels from the cell surface and a more rapid turnover rate than the wild type channels, which was evident very early in biogenesis. This study reveals a novel role of the COOH terminus in the normal biogenesis of HERG channels and suggests defective trafficking as a common mechanism for abnormal channel function resulting from mutations of critical COOH-terminal residues, including the LQTS mutant HERGN861I.
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Armin
authors.initials: A
authors.lastname: Akhavan
authors.forename: Roxana
authors.initials: R
authors.lastname: Atanasiu
authors.forename: Alvin
authors.initials: A
authors.lastname: Shrier
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001693:Biological Transport, Active; D027682:Cation Transport Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004721:Endoplasmic Reticulum / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels; D015870:Gene Expression; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D020836:Protein Structure, Quaternary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection
chemical_list: 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; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG