ArticleProceedings of the National Academy of Sciences of the United States of America2015
Four basic residues critical for the ion selectivity and pore blocker sensitivity of TMEM16A calcium-activated chloride channels.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 84 citations in OpenAlex.
- TMEM16A channel signalling microdomains in the regulation of vascular function.The Journal of physiology · 2026Review
- Conformational changes upon pore blocker removal reveal conductive states of TMEM16A.bioRxiv : the preprint server for biology · 2026Article
- Simulation-based survey of TMEM16 family reveals that robust lipid scrambling requires an open groove.eLife · 2025Article
- [Transmembrane protein 16A--a new target for the treatment of airway inflammatory diseases].Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery · 2025Review
- Calcium-activated chloride channel TMEM16A opens via pi-helical transition in transmembrane segment 4.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Simulation-based survey of TMEM16 family reveals that robust lipid scrambling requires an open groove.bioRxiv : the preprint server for biology · 2025Article
- Tamsulosin ameliorates bone loss by inhibiting the release of ClProceedings of the National Academy of Sciences of the United States of America · 2025Article
- The evolution of patch-clamp electrophysiology: Robotic, multiplex, and dynamic.Molecular pharmacology · 2025Review
- Distinct modulation of calcium-activated chloride channel TMEM16A by drug-binding sites.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Two serial filters control P2X7 cation selectivity, Ser342 in the central pore and lateral acidic residues at the cytoplasmic interface.PNAS nexus · 2024Article
- Niclosamide potentiates TMEM16A and induces vasoconstriction.The Journal of general physiology · 2024Article
- Structure and Function of Calcium-Activated Chloride Channels and Phospholipid Scramblases in the TMEM16 Family.Handbook of experimental pharmacology · 2024Review
- Function and Regulation of the Calcium-Activated Chloride Channel Anoctamin 1 (TMEM16A).Handbook of experimental pharmacology · 2024Article
- Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.The EMBO journal · 2023Article
- Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase.Nature communications · 2023Article
- Gating and anion selectivity are reciprocally regulated in TMEM16A (ANO1).The Journal of general physiology · 2022Article
- Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC.Nature communications · 2022Article
- Phospholipid scrambling by a TMEM16 homolog of Arabidopsis thaliana.The FEBS journal · 2022Article
- Polymodal Control of TMEM16x Channels and Scramblases.International journal of molecular sciences · 2022Review
- An outer-pore gate modulates the pharmacology of the TMEM16A channel.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
TMEM16A (transmembrane protein 16) (Anoctamin-1) forms a calcium-activated chloride channel (CaCC) that regulates a broad array of physiological properties in response to changes in intracellular calcium concentration. Although known to conduct anions according to the Eisenman type I selectivity sequence, the structural determinants of TMEM16A anion selectivity are not well-understood. Reasoning that the positive charges on basic residues are likely contributors to anion selectivity, we performed whole-cell recordings of mutants with alanine substitution for basic residues within the putative pore region and identified four residues on four different putative transmembrane segments that significantly increased the permeability of the larger halides and thiocyanate relative to that of chloride. Because TMEM16A permeation properties are known to shift with changes in intracellular calcium concentration, we further examined the calcium dependence of anion selectivity. We found that WT TMEM16A but not mutants with alanine substitution at those four basic residues exhibited a clear decline in the preference for larger anions as intracellular calcium was increased. Having implicated these residues as contributing to the TMEM16A pore, we scrutinized candidate small molecules from a high-throughput CaCC inhibitor screen to identify two compounds that act as pore blockers. Mutations of those four putative pore-lining basic residues significantly altered the IC50 of these compounds at positive voltages. These findings contribute to our understanding regarding anion permeation of TMEM16A CaCC and provide valuable pharmacological tools to probe the channel pore.
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