ArticleProceedings of the National Academy of Sciences of the United States of America2008
The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 130 citations in OpenAlex.
- Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.Clinical pharmacology and therapeutics · 2019Trial
- Characterization of Next-Generation Inhibitors for the Inward-Rectifier Potassium Channel KACS medicinal chemistry letters · 2025Article
- Self-assembling dendrimer nanodrug formulations for decreased hERG-related toxicity and enhanced therapeutic efficacy.Science advances · 2025Article
- Cardiovascular adverse effects of antiviral therapies for COVID-19: Evidence and plausible mechanisms.Acta pharmacologica Sinica · 2025Review
- Barium and psoriasis: a mini-review and hypothesis linking environmental exposures to ion channel modulation.Frontiers in medicine · 2025Review
- Review
- The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3.Cardiovascular research · 2024Article
- 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
- Clinical and electrocardiographic outcomes evaluated by telemedicine of outpatients with clinical suspicion of COVID-19 treated with chloroquine compounds in BrazilFrontiers in cardiovascular medicine · 2023Article
- Anti-malarial drugs: Mechanisms underlying their proarrhythmic effects.British journal of pharmacology · 2022Review
- In vitro ion channel profile and ex vivo cardiac electrophysiology properties of the R(-) and S(+) enantiomers of hydroxychloroquine.European journal of pharmacology · 2022Article
- Antiviral and anti-inflammatory drugs to combat COVID-19: Effects on cardiac ion channels and risk of ventricular arrhythmias.BioImpacts : BI · 2022Review
- Challenges and innovation: Disease modeling using human-induced pluripotent stem cell-derived cardiomyocytes.Frontiers in cardiovascular medicine · 2022Review
- Assessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA concept.European journal of pharmacology · 2021Article
- Cardiac potassium inward rectifier Kir2: Review of structure, regulation, pharmacology, and arrhythmogenesis.Heart rhythm · 2021Review
- Does hydroxychloroquine still have any role in the COVID-19 pandemic?Expert opinion on pharmacotherapy · 2021Article
- Drug-induced organ injury in coronavirus disease 2019 pharmacotherapy: Mechanisms and challenges in differential diagnosis and potential protective strategies.Journal of biochemical and molecular toxicology · 2021Review
- Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.American journal of physiology. Cell physiology · 2021Review
- Effect of Hydroxychloroquine on QTc in Patients Diagnosed with COVID-19: A Systematic Review and Meta-Analysis.Journal of cardiovascular development and disease · 2021Review
19 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
Although chloroquine remains an important therapeutic agent for treatment of malaria in many parts of the world, its safety margin is very narrow. Chloroquine inhibits the cardiac inward rectifier K(+) current I(K1) and can induce lethal ventricular arrhythmias. In this study, we characterized the biophysical and molecular basis of chloroquine block of Kir2.1 channels that underlie cardiac I(K1). The voltage- and K(+)-dependence of chloroquine block implied that the binding site was located within the ion-conduction pathway. Site-directed mutagenesis revealed the location of the chloroquine-binding site within the cytoplasmic pore domain rather than within the transmembrane pore. Molecular modeling suggested that chloroquine blocks Kir2.1 channels by plugging the cytoplasmic conduction pathway, stabilized by negatively charged and aromatic amino acids within a central pocket. Unlike most ion-channel blockers, chloroquine does not bind within the transmembrane pore and thus can reach its binding site, even while polyamines remain deeper within the channel vestibule. These findings explain how a relatively low-affinity blocker like chloroquine can effectively block I(K1) even in the presence of high-affinity endogenous blockers. Moreover, our findings provide the structural framework for the design of safer, alternative compounds that are devoid of Kir2.1-blocking properties.
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