ArticleAmerican journal of physiology. Cell physiology2011
Trafficking-deficient hERG K⁺ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER.
Article in American journal of physiology. Cell physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Functional characterization and allele-specific RNA interference-based rescue of KCNH2 p.F68C variant associated with long QT syndrome.Molecular genetics and genomics : MGG · 2026Article
- Ligand-based virtual-screening identified a novel CFTR ligand which improves the defective cell surface expression of misfolded ABC transporters.Frontiers in pharmacology · 2024Article
- The cellular pathways that maintain the quality control and transport of diverse potassium channels.Biochimica et biophysica acta. Gene regulatory mechanisms · 2023Article
- Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations.Communications biology · 2021Article
- Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in theCirculation. Arrhythmia and electrophysiology · 2018Article
- Development of a High-Throughput Flow Cytometry Assay to Monitor Defective Trafficking and Rescue of Long QT2 Mutant hERG Channels.Frontiers in physiology · 2018Article
- Visualizing Mutation-Specific Differences in the Trafficking-Deficient Phenotype of Kv11.1 Proteins Linked to Long QT Syndrome Type 2.Frontiers in physiology · 2018Article
- Potassium channels in the heart: structure, function and regulation.The Journal of physiology · 2017Review
- Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells.PloS one · 2017Article
- A rare schizophrenia risk variant of CACNA1I disrupts CaScientific reports · 2016Article
- Molecular pathogenesis of long QT syndrome type 2.Journal of arrhythmia · 2016Review
- Schizophrenia-Associated hERG channel Kv11.1-3.1 Exhibits a Unique Trafficking Deficit that is Rescued Through Proteasome Inhibition for High Throughput Screening.Scientific reports · 2016Article
- Electrophysiological Characteristics of the LQT2 Syndrome MutationFrontiers in physiology · 2016Article
- Mouse ERG K(+) channel clones reveal differences in protein trafficking and function.Journal of the American Heart Association · 2014Article
- Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects.Acta pharmacologica Sinica · 2014Review
- Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome.The EMBO journal · 2013Article
- Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum.American journal of physiology. Cell physiology · 2013Article
- Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.The Journal of membrane biology · 2013Article
- Article
- Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma.Oncogene · 2012Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The human ether-a-go-go related gene (hERG) encodes the voltage-gated K(+) channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an "immature" N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2.
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