ArticleAssay and drug development technologies
Development and validation of fluorescence-based and automated patch clamp-based functional assays for the inward rectifier potassium channel Kir4.1.
Article in Assay and drug development technologies. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Inhibition of SARS-CoV-2 Viral Channel Activity Using FDA-Approved Channel Modulators Independent of Variants.Biomolecules · 2022Article
- VU6036720: The First Potent and Selective In Vitro Inhibitor of Heteromeric Kir4.1/5.1 Inward Rectifier Potassium Channels.Molecular pharmacology · 2022Article
- Detecting SARS-CoV-2 Orf3a and E ion channel activity in COVID-19 blood samples.Journal of clinical and translational science · 2021Article
- Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels.ACS chemical neuroscience · 2019Article
- Distal tubule basolateral potassium channels: cellular and molecular mechanisms of regulation.Current opinion in nephrology and hypertension · 2018Review
- Rhodol-based thallium sensors for cellular imaging of potassium channel activity.Organic & biomolecular chemistry · 2018Article
- Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992.Molecular pharmacology · 2018Article
- Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx.ACS chemical neuroscience · 2017Article
- An insecticide resistance-breaking mosquitocide targeting inward rectifier potassium channels in vectors of Zika virus and malaria.Scientific reports · 2016Article
- ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels.ACS chemical neuroscience · 2016Article
- Novel KCNQ2 channel activators discovered using fluorescence-based and automated patch-clamp-based high-throughput screening techniques.Acta pharmacologica Sinica · 2016Article
- High throughput screening technologies for ion channels.Acta pharmacologica Sinica · 2016Review
- Tethered protein display identifies a novel Kir3.2 (GIRK2) regulator from protein scaffold libraries.ACS chemical neuroscience · 2014Article
- Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels.PloS one · 2014Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The inward rectifier potassium (Kir) channel Kir4.1 plays essential roles in modulation of neurotransmission and renal sodium transport and may represent a novel drug target for temporal lobe epilepsy and hypertension. The molecular pharmacology of Kir4.1 is limited to neurological drugs, such as fluoxetine (Prozac(©)), exhibiting weak and nonspecific activity toward the channel. The development of potent and selective small-molecule probes would provide critically needed tools for exploring the integrative physiology and therapeutic potential of Kir4.1. A fluorescence-based thallium (Tl(+)) flux assay that utilizes a tetracycline-inducible T-Rex-HEK293-Kir4.1 cell line to enable high-throughput screening (HTS) of small-molecule libraries was developed. The assay is dimethyl sulfoxide tolerant and exhibits robust screening statistics (Z'=0.75±0.06). A pilot screen of 3,655 small molecules and lipids revealed 16 Kir4.1 inhibitors (0.4% hit rate). 3,3-Diphenyl-N-(1-phenylethyl)propan-1-amine, termed VU717, inhibits Kir4.1-mediated thallium flux with an IC50 of ∼6 μM. An automated patch clamp assay using the IonFlux HT workbench was developed to facilitate compound characterization. Leak-subtracted ensemble "loose patch" recordings revealed robust tetracycline-inducible and Kir4.1 currents that were inhibited by fluoxetine (IC50=10 μM), VU717 (IC50=6 μM), and structurally related calcium channel blocker prenylamine (IC50=6 μM). Finally, we demonstrate that VU717 inhibits Kir4.1 channel activity in cultured rat astrocytes, providing proof-of-concept that the Tl(+) flux and IonFlux HT assays can enable the discovery of antagonists that are active against native Kir4.1 channels.
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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.