ArticlePflugers Archiv : European journal of physiology2016
Revealing the activation pathway for TMEM16A chloride channels from macroscopic currents and kinetic models.
Article in Pflugers Archiv : European journal of physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.
- ANO1: More Than Just Calcium-Activated Chloride Channel in Cancer.Frontiers in oncology · 2022Pooled it
- CFTR-driven immune microenvironment reprogramming synergizes with anti-PD-L1 antibody in hepatocellular carcinoma.Cell death & disease · 2026Article
- 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
- The emerging role of anoctamin-1 in cardiac and cerebrovascular diseases.Frontiers in cardiovascular medicine · 2025Review
- Structure and Function of Calcium-Activated Chloride Channels and Phospholipid Scramblases in the TMEM16 Family.Handbook of experimental pharmacology · 2024Review
- Gating and anion selectivity are reciprocally regulated in TMEM16A (ANO1).The Journal of general physiology · 2022Article
- Role of ANO1 in tumors and tumor immunity.Journal of cancer research and clinical oncology · 2022Review
- Polymodal Control of TMEM16x Channels and Scramblases.International journal of molecular sciences · 2022Review
- Positive modulation of the TMEM16B mediated currents by TRPV4 antagonist.Biochemistry and biophysics reports · 2021Article
- Emerging Modulators of TMEM16A and Their Therapeutic Potential.The Journal of membrane biology · 2021Review
- Structure and Function of Ion Channels Regulating Sperm Motility-An Overview.International journal of molecular sciences · 2021Review
- Mechanism of pore opening in the calcium-activated chloride channel TMEM16A.Nature communications · 2021Article
- Local CaScience signaling · 2020Article
- Article
- Recent progress in structural studies on TMEM16A channel.Computational and structural biotechnology journal · 2020Review
- Calcium-Activated Chloride Channel ANO1/TMEM16A: Regulation of Expression and Signaling.Frontiers in physiology · 2020Review
- The multifaceted role of TMEM16A in cancer.Cell calcium · 2019Review
- The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel.Neuron · 2018Article
- Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1).Biochimica et biophysica acta. Molecular and cell biology of lipids · 2018Article
- Extracellular protons enable activation of the calcium-dependent chloride channel TMEM16A.The Journal of physiology · 2017Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
TMEM16A (ANO1), the pore-forming subunit of calcium-activated chloride channels, regulates several physiological and pathophysiological processes such as smooth muscle contraction, cardiac and neuronal excitability, salivary secretion, tumour growth and cancer progression. Gating of TMEM16A is complex because it involves the interplay between increases in intracellular calcium concentration ([Ca(2+)]i), membrane depolarization, extracellular Cl(-) or permeant anions and intracellular protons. Our goal here was to understand how these variables regulate TMEM16A gating and to explain four observations. (a) TMEM16A is activated by voltage in the absence of intracellular Ca(2+). (b) The Cl(-) conductance is decreased after reducing extracellular Cl(-) concentration ([Cl(-)]o). (c) ICl is regulated by physiological concentrations of [Cl(-)]o. (d) In cells dialyzed with 0.2 μM [Ca(2+)]i, Cl(-) has a bimodal effect: at [Cl(-)]o <30 mM TMEM16A current activates with a monoexponential time course, but above 30 mM, [Cl(-)]o ICl activation displays fast and slow kinetics. To explain the contribution of Vm, Ca(2+) and Cl(-) to gating, we developed a 12-state Markov chain model. This model explains TMEM16A activation as a sequential, direct, and Vm-dependent binding of two Ca(2+) ions coupled to a Vm-dependent binding of an external Cl(-) ion, with Vm-dependent transitions between states. Our model predicts that extracellular Cl(-) does not alter the apparent Ca(2+) affinity of TMEM16A, which we corroborated experimentally. Rather, extracellular Cl(-) acts by stabilizing the open configuration induced by Ca(2+) and by contributing to the Vm dependence of activation.
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Registered trials
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.