ArticleBritish journal of pharmacology2010
Identification of sites responsible for the potentiating effect of niflumic acid on ClC-Ka kidney chloride channels.
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 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Pleiotropic Effects of the NSAID Fenamates on Chloride Channels: Opportunity for Ion Channelopathies?Pharmacology research & perspectives · 2025Review
- Small Molecules Targeting Kidney ClC-K Chloride Channels: Applications in Rare Tubulopathies and Common Cardiovascular Diseases.Biomolecules · 2023Review
- Properties of single-channel and whole cell ClAmerican journal of physiology. Cell physiology · 2019Article
- New Insights into the Mechanism of NOJournal of the American Society of Nephrology : JASN · 2019Article
- Mapping ligand binding pockets in chloride ClC-1 channels through an integrated in silico and experimental approach using anthracene-9-carboxylic acid and niflumic acid.British journal of pharmacology · 2018Article
- In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening.Scientific reports · 2017Article
- Reduced Membrane Insertion of CLC-K by V33L Barttin Results in Loss of Hearing, but Leaves Kidney Function Intact.Frontiers in physiology · 2017Article
- Voltage-Dependent Inhibition of Glycine Receptor Channels by Niflumic Acid.Frontiers in molecular neuroscience · 2017Article
- Regulatory-auxiliary subunits of CLC chloride channel-transport proteins.The Journal of physiology · 2015Review
- I-J loop involvement in the pharmacological profile of CLC-K channels expressed in Xenopus oocytes.Biochimica et biophysica acta · 2014Article
- Novel diuretic targets.American journal of physiology. Renal physiology · 2013Review
- Alkaline pH block of CLC-K kidney chloride channels mediated by a pore lysine residue.Biophysical journal · 2013Article
- Flufenamic acid as an ion channel modulator.Pharmacology & therapeutics · 2013Review
- A regulatory calcium-binding site at the subunit interface of CLC-K kidney chloride channels.The Journal of general physiology · 2010Article
- Molecular Pharmacology of Kidney and Inner Ear CLC-K Chloride Channels.Frontiers in pharmacology · 2010Article
- Physiology and pathophysiology of ClC-K/barttin channels.Frontiers in physiology · 2010Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
background and purposeClC-K kidney Cl(-) channels are important for renal and inner ear transepithelial Cl(-) transport, and are potentially interesting pharmacological targets. They are modulated by niflumic acid (NFA), a non-steroidal anti-inflammatory drug, in a biphasic way: NFA activates ClC-Ka at low concentrations, but blocks the channel above approximately 1 mM. We attempted to identify the amino acids involved in the activation of ClC-Ka by NFA. EXPERIMENTAL APPROACH: We used site-directed mutagenesis and two-electrode voltage clamp analysis of wild-type and mutant channels expressed in Xenopus oocytes. Guided by the crystal structure of a bacterial CLC homolog, we screened 97 ClC-Ka mutations for alterations of NFA effects. KEY
resultsMutations of five residues significantly reduced the potentiating effect of NFA. Two of these (G167A and F213A) drastically altered general gating properties and are unlikely to be involved in NFA binding. The three remaining mutants (L155A, G345S and A349E) severely impaired or abolished NFA potentiation. CONCLUSIONS AND IMPLICATIONS: The three key residues identified (L155, G345, A349) are localized in two different protein regions that, based on the crystal structure of bacterial CLC homologs, are expected to be exposed to the extracellular side of the channel, relatively close to each other, and are thus good candidates for being part of the potentiating NFA binding site. Alternatively, the protein region identified mediates conformational changes following NFA binding. Our results are an important step towards the development of ClC-Ka activators for treating Bartter syndrome types III and IV with residual channel activity.
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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.