ArticleBritish journal of pharmacology2010
The anti-protozoal drug pentamidine blocks KIR2.x-mediated inward rectifier current by entering the cytoplasmic pore region of the channel.
Article in British journal of pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 43 citations in OpenAlex.
- A Novel KCNJ2 p.Glu299Ala Variant Associated with Short QT Phenotype and Persistent Atrial Fibrillation in a Child.Life (Basel, Switzerland) · 2026Article
- Structural analysis of ITS 1 gene ofFrontiers in cellular and infection microbiology · 2026Article
- The network of cardiac KNaunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIPNaunyn-Schmiedeberg's archives of pharmacology · 2023Article
- Chronic Propafenone Application Increases Functional KPharmaceuticals (Basel, Switzerland) · 2023Article
- Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.American journal of physiology. Cell physiology · 2021Review
- Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug.PLoS neglected tropical diseases · 2021Article
- Development of IFrontiers in pharmacology · 2021Article
- Computational Identification of Novel Kir6 Channel Inhibitors.Frontiers in pharmacology · 2019Article
- The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models.British journal of pharmacology · 2017Article
- PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function KJournal of biomedical science · 2017Article
- Inhibition of inwardly rectifying Kir2.x channels by the novel anti-cancer agent gambogic acid depends on both pore block and PIPNaunyn-Schmiedeberg's archives of pharmacology · 2017Article
- Inhibition of Kir4.1 potassium channels by quinacrine.Brain research · 2017Article
- ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels.ACS chemical neuroscience · 2016Article
- Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness.Physiological reports · 2016Article
- Pentamidine analogs as inhibitors of [(3)H]MK-801 and [(3)H]ifenprodil binding to rat brain NMDA receptors.Bioorganic & medicinal chemistry · 2015Article
- Class III antiarrhythmic drug dronedarone inhibits cardiac inwardly rectifying Kir2.1 channels through binding at residue E224.Naunyn-Schmiedeberg's archives of pharmacology · 2014Article
- Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics.Current opinion in pharmacology · 2014Review
- Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue.British journal of pharmacology · 2013Article
- KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposePentamidine is a drug used in treatment of protozoal infections. Pentamidine treatment may cause sudden cardiac death by provoking cardiac arrhythmias associated with QTc prolongation and U-wave alterations. This proarrhythmic effect was linked to inhibition of hERG trafficking, but not to acute block of ion channels contributing to the action potential. Because the U-wave has been linked to the cardiac inward rectifier current (I(K1)), we examined the action and mechanism of pentamidine-mediated I(K1) block. EXPERIMENTAL APPROACH: Patch clamp measurements of I(K1) were made on cultured adult canine ventricular cardiomyocytes, K(IR)2.1-HEK293 cells and K(IR)2.x inside-out patches. Pentamidine binding to cytoplasmic amino acid residues of K(IR)2.1 channels was studied by molecular modelling. KEY
resultsPentamidine application (24 h) decreased I(K1) in cultured canine cardiomyocytes and K(IR)2.1-HEK293 cells under whole cell clamp conditions. Pentamidine inhibited I(K1) in K(IR)2.1-HEK293 cells 10 min after application. When applied to the cytoplasmic side under inside-out patch clamp conditions, pentamidine block of I(K1) was acute (IC(50)= 0.17 microM). Molecular modelling predicted pentamidine-channel interactions in the cytoplasmic pore region of K(IR)2.1 at amino acids E224, D259 and E299. Mutation of these conserved residues to alanine reduced pentamidine block of I(K1). Block was independent of the presence of spermine. K(IR)2.2, and K(IR)2.3 based I(K1) was also sensitive to pentamidine blockade. CONCLUSIONS AND IMPLICATIONS: Pentamidine inhibits cardiac I(K1) by interacting with three negatively charged amino acids in the cytoplasmic pore region. Our findings may provide new insights for development of specific I(K1) blocking compounds.
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