ArticleMolecular pharmacology2009
Intracellular potassium stabilizes human ether-à-go-go-related gene channels for export from endoplasmic reticulum.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 31 citations in OpenAlex.
- Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome.Frontiers in pharmacology · 2020Review
- Mutation-specific peripheral and ER quality control of hERG channel cell-surface expression.Scientific reports · 2019Article
- Voltage-gated sodium channels assemble and gate as dimers.Nature communications · 2017Article
- (+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks.Journal of natural products · 2017Article
- Molecular pathogenesis of long QT syndrome type 2.Journal of arrhythmia · 2016Review
- Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects.Acta pharmacologica Sinica · 2014Review
- Pharmacological chaperoning: a primer on mechanism and pharmacology.Pharmacological research · 2014Review
- Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane.Molecular biology of the cell · 2013Article
- Molecular determinants of pentamidine-induced hERG trafficking inhibition.Molecular pharmacology · 2012Article
- Modulation of α(2C) adrenergic receptor temperature-sensitive trafficking by HSP90.Biochimica et biophysica acta · 2011Article
- hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine.Naunyn-Schmiedeberg's archives of pharmacology · 2011Article
- In vivo evidence for the involvement of the carboxy terminal domain in assembling connexin 36 at the electrical synapse.Molecular and cellular neurosciences · 2010Article
- Emerging concepts in the pharmacogenomics of arrhythmias: ion channel trafficking.Expert review of cardiovascular therapy · 2010Review
- Trafficking-competent KCNQ1 variably influences the function of HERG long QT alleles.Heart rhythm · 2010Article
- Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines.The Journal of clinical investigation · 2009Article
- Interaction of local anesthetics with the K (+) channel pore domain: KcsA as a model for drug-dependent tetramer stability.Channels (Austin, Tex.)Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Several therapeutic compounds have been identified that prolong the QT interval on the electrocardiogram and cause torsade de pointes arrhythmias not by direct block of the cardiac potassium channel human ether-à-go-go-related gene (hERG) but via disruption of hERG trafficking to the cell surface membrane. One example of a clinically important compound class that potently inhibits hERG trafficking are cardiac glycosides. We have shown previously that inhibition of hERG trafficking by cardiac glycosides is initiated via direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or any other protein. However, it was not known how pump inhibition at the cell surface is coupled to hERG processing in the endoplasmic reticulum. Here, we show that depletion of intracellular K(+)-either indirectly after long-term exposure to cardiac glycosides or directly after exposure to gramicidin in low sodium media-is sufficient to disrupt hERG trafficking. In K(+)-depleted cells, hERG trafficking can be restored by permeating K(+) or Rb(+) ions, incubation at low temperature, exposure to the pharmacological chaperone astemizole, or specific mutations in the selectivity filter of hERG. Our data suggest a novel mechanism for drug-induced trafficking inhibition in which cardiac glycosides produce a [K(+)](i)-mediated conformational defect directly in the hERG channel protein.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.