ArticleMolecular pharmacology2012
Molecular determinants of pentamidine-induced hERG trafficking inhibition.
Article in Molecular pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
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- Vicious LQT induced by a combination of factors different from hERG inhibition.Frontiers in pharmacology · 2022Article
- Detection and impact of hysteresis when evaluating a drug's QTc effect using concentration-QTc analysis.Journal of pharmacokinetics and pharmacodynamics · 2021Article
- Toward a broader view of mechanisms of drug cardiotoxicity.Cell reports. Medicine · 2021Review
- Probucol-induced hERG Channel Reduction can be Rescued by Matrine and OxymatrineCurrent pharmaceutical design · 2020Article
- Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells.Scientific reports · 2019Article
- Drug-likeness of linear pentamidine analogues and their impact on the hERG KRSC advances · 2019Article
- A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells.PloS one · 2017Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Pentamidine is an antiprotozoal compound that clinically causes acquired long QT syndrome (acLQTS), which is associated with prolonged QT intervals, tachycardias, and sudden cardiac arrest. Pentamidine delays terminal repolarization in human heart by acutely blocking cardiac inward rectifier currents. At the same time, pentamidine reduces surface expression of the cardiac potassium channel I(Kr)/human ether à-go-go-related gene (hERG). This is unusual in that acLQTS is caused most often by direct block of the cardiac potassium current I(Kr)/hERG. The present study was designed to provide a more complete picture of how hERG surface expression is disrupted by pentamidine at the cellular and molecular levels. Using biochemical and electrophysiological methods, we found that pentamidine exclusively inhibits hERG export from the endoplasmic reticulum to the cell surface in a heterologous expression system as well as in cardiomyocytes. hERG trafficking inhibition could be rescued in the presence of the pharmacological chaperone astemizole. We used rescue experiments in combination with an extensive mutational analysis to locate an interaction site for pentamidine at phenylalanine 656, a crucial residue in the canonical drug binding site of terminally folded hERG. Our data suggest that pentamidine binding to a folding intermediate of hERG arrests channel maturation in a conformational state that cannot be exported from the endoplasmic reticulum. We propose that pentamidine is the founding member of a novel pharmacological entity whose members act as small molecule antichaperones.
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