Affinage

ANO1

Anoctamin-1 · UniProt Q5XXA6

Length
986 aa
Mass
114.1 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANO1 (TMEM16A) is a Ca²⁺-activated chloride channel that functions as a constitutive homodimer to transduce local intracellular Ca²⁺ signals into Cl⁻/HCO₃⁻ efflux and membrane depolarization across diverse tissues including smooth muscle, epithelia, interstitial cells of Cajal, and pericytes (PMID:19965375, PMID:35316222). Channel gating requires sequential binding of two Ca²⁺ ions in a voltage-dependent manner, is allosterically stabilized by PI(4,5)P₂ at three cytoplasmic binding sites, and is modulated by calmodulin (which shifts anion selectivity toward HCO₃⁻), CaMKII phosphorylation at S528, and PKCα (PMID:27138167, PMID:31515451, PMID:23248295, PMID:31461344, PMID:26542395). ANO1 operates within macromolecular complexes with IP₃ receptors, TRPC6, and CaV1.2, coupling local Ca²⁺ release to depolarization-driven vascular tone and Ca²⁺ waves, and is required for basal mucus secretion, CFTR membrane expression, thyroid iodide efflux, and primary ciliogenesis (PMID:37702787, PMID:27147559, PMID:30586313, PMID:28963502, PMID:25298423, PMID:24694595). Rare gain-of-function ANO1 variants with increased Ca²⁺ sensitivity cause moyamoya disease, and ANO1 overexpression drives tumor proliferation through MAPK/ERK signaling and promotes ferroptosis resistance and chemoresistance via GPX4 degradation and lysosomal exocytosis pathways (PMID:37253099, PMID:22564524, PMID:36572666, PMID:35286200).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2009 High

    Establishing ANO1 as the molecular identity of the long-sought Ca²⁺-activated Cl⁻ channel in native tissues resolved decades of pharmacological characterization: knockout mice lacking TMEM16A lost rhythmic gastric contraction and CaCC activity in ICC, glandular epithelia, and smooth muscle.

    Evidence Immunohistochemistry with knockout-validated antibodies, tissue distribution, gastric contractility in TMEM16A knockout mice

    PMID:19965375

    Open questions at the time
    • Gating mechanism and Ca²⁺-sensing residues not yet identified
    • Oligomeric state unknown
    • Role in non-GI tissues not functionally tested in knockout
  2. 2010 High

    Demonstrating that ANO1 forms constitutive homodimers assembled before plasma membrane insertion established the basic quaternary architecture of the channel, independent of Ca²⁺.

    Evidence Co-immunoprecipitation, FRET, chemical cross-linking, and native PAGE in HEK293 cells

    PMID:21056985

    Open questions at the time
    • Stoichiometry of functional pore (one or two pores per dimer) unresolved
    • Dimerization interface not mapped
  3. 2012 High

    Two advances broadened ANO1 function beyond ion conduction: calmodulin was shown to switch anion selectivity toward HCO₃⁻ in a Ca²⁺-dependent manner, and ANO1 overexpression was found to activate ERK1/2-cyclin D1 signaling to drive tumor growth, establishing a non-channel oncogenic role.

    Evidence Excised patch reconstitution with recombinant calmodulin (selectivity); siRNA, dominant-negative ERK, MEK inhibitors, xenografts (MAPK signaling)

    PMID:22564524 PMID:23248295

    Open questions at the time
    • Direct calmodulin binding site on ANO1 not mapped
    • Mechanism linking ANO1 to ERK activation (channel-dependent or not) unclear
    • Whether selectivity switch occurs in all tissue contexts unknown
  4. 2013 Medium

    DOG1/ANO1 silencing in GIST xenografts delayed tumor growth and upregulated IGFBP5, suggesting ANO1 promotes tumor angiogenesis through IGF signaling modulation, extending its oncogenic reach beyond MAPK.

    Evidence RNAi silencing, GIST xenograft model, expression profiling

    PMID:23576565

    Open questions at the time
    • Direct mechanism linking channel activity to IGFBP5 transcription not established
    • Whether DOG1 channel function or protein scaffolding drives the effect unknown
  5. 2014 High

    A series of discoveries defined new physiological roles: ANO1 was shown to be the apical thyroid iodide channel regulated by TSH, to be required for primary ciliogenesis via a 'nimbus' structure enriched in Cdc42/exocyst, and to use its TM5–TM6 pore region for Cl⁻ conductance while the homologous region in TMEM16F mediates scramblase activity.

    Evidence RNAi and inhibitor in thyrocytes (iodide efflux); shRNA and pharmacological block (ciliogenesis); domain-swap mutagenesis between TMEM16A/F (pore function)

    PMID:24478309 PMID:24694595 PMID:25298423

    Open questions at the time
    • Mechanism by which Cl⁻ flux promotes cilia assembly unknown
    • Whether iodide permeates through the same pore as Cl⁻ not directly tested
    • Structural basis for functional divergence between TMEM16A and TMEM16F pores not resolved
  6. 2015 High

    Lipid regulation of ANO1 was established: PI(4,5)P₂ is required for channel function, cholesterol modulates activity through PI(4,5)P₂-independent mechanisms, and fatty acids inhibit the channel, while PKCα was separately shown to directly activate ANO1-mediated Cl⁻ secretion in biliary epithelia.

    Evidence Rapamycin-induced PI(4,5)P₂ depletion, cholesterol manipulation, fatty acid application with patch clamp; recombinant PKCα intracellular dialysis and siRNA in biliary cells

    PMID:26542395 PMID:29277655

    Open questions at the time
    • PKCα phosphorylation site(s) on ANO1 not identified
    • PI(4,5)P₂ binding sites not mapped at this stage
    • Whether lipid regulation operates in vivo under physiological conditions not shown
  7. 2016 High

    Quantitative gating analysis revealed that ANO1 activation involves sequential voltage-dependent binding of two Ca²⁺ ions coupled with extracellular Cl⁻ binding that stabilizes the open state, and TRPC6–ANO1 nanodomain coupling was demonstrated in cerebral arterial myocytes via BAPTA/EGTA chelation kinetics.

    Evidence 12-state Markov model validated by patch clamp (gating); co-IP, FRET, fast/slow chelator approach, pressurized artery myography (TRPC6 coupling)

    PMID:27138167 PMID:27147559

    Open questions at the time
    • Identity of Ca²⁺-coordinating residues not structurally confirmed at this point
    • Whether TRPC6–ANO1 coupling requires direct contact or intermediary scaffold unknown
  8. 2017 High

    Tissue-specific knockouts revealed that ANO1 is unexpectedly required for CFTR-mediated Cl⁻ secretion and CFTR membrane expression in airways and intestine, and ANO1 inhibits apoptosis through Bim downregulation in head and neck cancer.

    Evidence Intestinal and airway-specific TMEM16A knockout mice with Ussing chamber transport (CFTR); xenografts with Bim/ERK analysis (apoptosis)

    PMID:28899969 PMID:28963502

    Open questions at the time
    • Molecular mechanism by which ANO1 regulates CFTR trafficking not elucidated
    • Whether ANO1–CFTR interaction is direct or mediated by shared signaling platform unclear
    • Bim regulation mechanism downstream of ANO1-ERK is correlative
  9. 2018 High

    Cell-type-specific knockouts proved ANO1 is essential for basal and ATP-stimulated mucus secretion via membrane exocytosis in airway ciliated cells and intestinal goblet cells, distinguishing this from cholinergic compound exocytosis.

    Evidence FoxJ1-Cre and Vil1-Cre conditional knockouts, ATP-induced mucus secretion assays

    PMID:30586313

    Open questions at the time
    • How ANO1 channel activity triggers membrane exocytosis mechanistically unresolved
    • Role of Cl⁻ flux versus membrane depolarization versus direct protein interaction in exocytosis unclear
  10. 2019 High

    Three molecular regulatory mechanisms were defined: PI(4,5)P₂ allosterically stabilizes the open state through three discrete binding sites affecting TM6 position; CaMKII phosphorylation at S528 causes channel rundown balanced by PP1/PP2A; and SP1/MLL1-driven H3K4me3 controls ANO1 transcription in gastric cancer.

    Evidence Inside-out patch clamp with mutagenesis and atomistic MD simulations (PIP₂ sites); S528A mutagenesis with CaMKII/phosphatase inhibitors (phosphorylation); ChIP and reporter assays (transcription)

    PMID:30871776 PMID:31461344 PMID:31515451

    Open questions at the time
    • Whether all three PIP₂ sites must be simultaneously occupied unknown
    • Interplay between CaMKII and PKCα phosphorylation not addressed
    • SP1/MLL1 mechanism specific to gastric cancer or general not determined
  11. 2022 High

    ANO1's role extended to cerebrovascular pathology and ferroptosis: in pericytes, ANO1-mediated depolarization amplifies ischemia-evoked Ca²⁺ rise and capillary constriction, and its inhibition improved post-stroke reperfusion; separately, ANO1 interacts with GPX4 to promote its ubiquitination and degradation, enhancing ferroptosis in hepatocytes.

    Evidence Pericyte patch clamp and MCAO stroke model with two-photon imaging; co-IP, ubiquitination assays, hepatocyte-specific knockout (ferroptosis)

    PMID:35316222 PMID:36572666

    Open questions at the time
    • Whether ANO1–GPX4 interaction requires channel activity unknown
    • Identity of the E3 ligase mediating GPX4 ubiquitination downstream of ANO1 not identified
    • Pericyte-specific knockout not performed
  12. 2023 High

    ANO1 was shown to form a tripartite macromolecular complex with CaV1.2 and IP₃R in pulmonary artery smooth muscle that is essential for serotonin-induced tone and Ca²⁺ waves, and rare gain-of-function ANO1 variants with enhanced Ca²⁺ sensitivity were identified as a genetic cause of moyamoya disease.

    Evidence Smooth muscle-specific ablation, co-IP, superresolution microscopy, Ca²⁺ imaging (complex); exome sequencing and patch clamp of variant channels (moyamoya)

    PMID:37253099 PMID:37702787

    Open questions at the time
    • Structural basis of the ANO1–CaV1.2–IP₃R complex not determined
    • Whether moyamoya variants affect channel expression, trafficking, or only gating not fully explored
    • Vascular cell type(s) driving moyamoya pathology not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how ANO1 channel activity is mechanistically linked to MAPK/ERK activation and tumor proliferation (channel-dependent versus scaffolding); the structural basis for lipid-gated conformational changes; and whether the non-channel functions (ciliogenesis, ferroptosis regulation, exocytosis) require ion conduction or represent independent protein–protein interaction roles.
  • No separation of channel-dependent vs channel-independent oncogenic functions
  • No high-resolution structure of full-length mammalian ANO1 with PIP₂ and Ca²⁺ bound simultaneously
  • Mechanism connecting Cl⁻ flux to membrane exocytosis and ciliogenesis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 14 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 6 GO:0005929 cilium 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-382551 Transport of small molecules 5 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 3
Partners
CACNA1CCFTREZRGPX4ITPR1LRRC8ATRPC6
Complex memberships
ANO1–CaV1.2–IP3R complexANO1–TRPC6 nanodomain complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 TMEM16A (ANO1) is localized to the apical membranes of epithelial cells in exocrine glands and trachea, expressed in airway smooth muscle cells and reproductive tract smooth muscle, and present in interstitial cells of Cajal (ICC) in the GI tract; knockout mice show diminished rhythmic gastric smooth muscle contraction, establishing TMEM16A as the functional Ca2+-activated chloride channel subunit in these tissues. Antibody validation in knockout mice, immunohistochemistry, tissue-specific expression analysis, gastric contractility assay in TMEM16A knockout mice Proceedings of the National Academy of Sciences of the United States of America High 19965375
2012 ANO1/TMEM16A overexpression activates ERK1/2 and induces cyclin D1 upregulation to promote cancer cell proliferation and tumor growth; pharmacologic MEK/ERK inhibition or genetic inactivation of ERK1/2 abrogates this growth effect, placing TMEM16A upstream of the MAPK pathway in tumorigenesis. siRNA knockdown, dominant-negative ERK constructs, pharmacologic MEK/ERK inhibition, in vitro growth assays, in vivo xenograft models Cancer research High 22564524
2012 ANO1/TMEM16A anion selectivity is dynamically regulated by Ca2+/calmodulin: at high intracellular Ca2+, calmodulin physically associates with ANO1 in a Ca2+-dependent manner, increasing HCO3- permeability relative to Cl-; this was shown to be a cytosol-dependent process absent in excised patches but restored by adding recombinant calmodulin. Whole-cell patch clamp, excised inside-out patch recordings, addition of recombinant calmodulin, HEK293T cells and mouse submandibular gland acinar cells Proceedings of the National Academy of Sciences of the United States of America High 23248295
2010 ANO1/TMEM16A forms a homodimer in the plasma membrane; subunits associate before reaching the plasma membrane, and this association is not altered by changes in cytosolic Ca2+, indicating a constitutive fixed interaction. Co-immunoprecipitation, FRET with mCherry- and eGFP-tagged ANO1, chemical cross-linking, non-denaturing PAGE, electromobility shift assay The Journal of biological chemistry High 21056985
2019 ANO1/TMEM16A channel gating is allosterically regulated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] through a network of three binding sites at the cytoplasmic face of the membrane; PI(4,5)P2 stabilizes the Ca2+-bound open state by altering the position of the cytoplasmic extension of TM6 and increasing inner vestibule accessibility to Cl- ions. Electrophysiology (inside-out patch clamp), mutagenesis of basic residues, unbiased atomistic molecular dynamics simulations, functional assays Proceedings of the National Academy of Sciences of the United States of America High 31515451
2014 ANO1/TMEM16A is located in the primary cilium and is required for primary ciliogenesis; before ciliogenesis, ANO1 organizes into a torus-shaped 'nimbus' structure enriched in Cdc42, Arl13b, and the exocyst component Sec6, and pharmacological blockade or shRNA knockdown of ANO1 impairs cilium formation. Immunofluorescence microscopy, shRNA knockdown, pharmacological inhibition, live-cell imaging Molecular biology of the cell High 24694595
2014 ANO1/TMEM16A is the major apical iodide channel of thyrocytes; TSH stimulates ANO1 expression and accumulation at the apical membrane of thyroid follicles, and ANO1-specific inhibitor T16Ainh-A01 or ANO1 knockdown by RNAi blocks iodide release in rat thyroid cell lines and human thyrocytes. ANO1-specific inhibitor, RNAi knockdown, iodide efflux assays, immunohistochemistry, intracellular calcium activation assays American journal of physiology. Cell physiology High 25298423
2014 ANO1/TMEM16A channels are activated by localized Ca2+ signals from intracellular Ca2+ stores, particularly at IP3-receptor-dependent Ca2+ release sites; this local coupling represents a general mechanism for ANO1 activation in native tissues at physiologically relevant global Ca2+ concentrations. Electrophysiology, immunolocalization, pharmacological characterization of Ca2+ source dependence, review of co-localization evidence across cell types The Journal of physiology Medium 25398532
2016 ANO1/TMEM16A channels in cerebral arterial myocytes are in close physical proximity to TRPC6 channels; TRPC6 activation generates a local Ca2+ signal that activates adjacent ANO1 channels to stimulate vasoconstriction, as BAPTA (a fast Ca2+ chelator) but not EGTA abolishes this coupling. Co-immunoprecipitation, immunofluorescence FRET microscopy, whole-cell and single-channel patch clamp, BAPTA vs EGTA chelation, siRNA knockdown, TRPC6-selective activator Hyp9, ANO1 inhibitor T16Ainh-A01, pressurized artery myography American journal of physiology. Cell physiology High 27147559
2015 PKCα regulates TMEM16A-mediated Cl- secretion in biliary epithelial cells: ATP stimulates PKCα translocation to the plasma membrane, and intracellular dialysis with recombinant PKCα activates Cl- currents identical to TMEM16A, while PKCα siRNA or pharmacological inhibition suppresses TMEM16A currents. Whole-cell patch clamp, PKCα siRNA, pharmacological inhibitors, intracellular dialysis with recombinant PKCα, TMEM16A siRNA American journal of physiology. Gastrointestinal and liver physiology High 26542395
2017 CFTR chloride transport in airway and intestinal epithelium requires TMEM16A: tissue-specific knockout of TMEM16A eliminates both Ca2+-activated Cl- currents and cAMP-activated CFTR-mediated Cl- secretion; TMEM16A provides a mechanism for enhanced ER Ca2+ store release engaging Store Operated cAMP Signaling (SOcAMPS) and is essential for proper CFTR membrane expression. Tissue-specific knockout mice (intestinal and airway ciliated cell-specific), Ussing chamber Cl- transport measurements, whole-cell currents Scientific reports High 28963502
2019 ANO1/TMEM16A channel activity is regulated by CaMKII-mediated phosphorylation at serine 528, and by protein phosphatases PP1/PP2A; CaMKII causes channel rundown while PP1/PP2A inhibition promotes rundown, and S528A mutation mimics CaMKII inhibition, preventing rundown. Whole-cell patch clamp in HEK-293 cells, CaMKII inhibitors (AIP, KN-93), phosphatase inhibitors (okadaic acid, cantharidin), site-directed mutagenesis (S528A and other sites) American journal of physiology. Cell physiology High 31461344
2015 ANO1/TMEM16A channels in arterial smooth muscle are blocked by 9-phenanthrol; 9-phenanthrol reduces single-channel ANO1 open probability and mean open time without affecting conductance amplitude, revealing a mechanism of block distinct from TRPM4 inhibition and explaining the compound's ability to abolish myogenic tone. Patch-clamp electrophysiology (whole-cell and cell-attached) in rat cerebral artery myocytes and HEK293 cells expressing recombinant human TMEM16A, comparison with bestrophin-1 expressing cells British journal of pharmacology High 25573456
2011 CFTR and TMEM16A are separate molecular entities that physically interact (co-immunoprecipitation) and functionally inhibit each other: CFTR activation attenuates TMEM16A currents, and TMEM16A expression attenuates CFTR currents; both are membrane localized. Co-immunoprecipitation, whole-cell patch clamp, CFTR and TMEM16A co-expression in HEK293 cells and human airway epithelial cells Cellular physiology and biochemistry Medium 22178883
2013 DOG1/TMEM16A generates functional Ca2+-activated Cl- currents in GIST cells that can be pharmacologically regulated; DOG1 silencing in GIST xenografts delays tumor growth in vivo and upregulates IGFBP5, a potent anti-angiogenic factor, implicating modulation of IGF/IGFR signaling in the tumor microenvironment as an oncogenic mechanism. RNAi silencing, pharmacological inhibition, xenograft model, expression profiling of explanted tumors, selection of imatinib-resistant DOG1-negative cells Cancer research Medium 23576565
2014 TMEM16A and TMEM16F each form homodimers; their cytoplasmic N-terminal and C-terminal regions are essential for plasma membrane localization and protein stability respectively and are exchangeable between family members; the pore region between TM5 and TM6 is essential for both Cl- channel activity (TMEM16A) and phospholipid scramblase activity (TMEM16F). Chemical cross-linking, deletion analysis, domain swapping, point mutagenesis in pore region, functional assays in 293T cells and TMEM16F-/- thymocytes The Journal of biological chemistry High 24478309
2016 ANO1/TMEM16A gating follows a sequential, voltage-dependent binding of two Ca2+ ions coupled to a voltage-dependent binding of an external Cl- ion; extracellular Cl- does not alter Ca2+ affinity but stabilizes the open configuration and contributes to voltage dependence of activation. Whole-cell patch clamp, macroscopic current analysis, 12-state Markov chain kinetic modeling, experimental validation of model predictions Pflugers Archiv : European journal of physiology High 27138167
2016 HCO3- transport through ANO1/TMEM16A in pancreatic acinar cells regulates intraluminal pH; under physiological CCK stimulation, the T16Ainh-A01-sensitive (ANO1-dependent) pathway blunts luminal acidification caused by zymogen granule exocytosis, and ANO1 also attenuates luminal acidification in acute pancreatitis models. Intraluminal pH measurement in freshly isolated pancreatic acini preserving luminal structure, pharmacological ANO1 inhibition with T16inh-A01 The Journal of biological chemistry Medium 27510033
2022 In pericytes, TMEM16A mediates a Ca2+-activated chloride efflux that depolarizes the cell, opens voltage-gated calcium channels, and strongly amplifies the pericyte Ca2+ rise and capillary constriction; in a rodent stroke model, TMEM16A inhibition slowed ischemia-evoked Ca2+ rise, capillary constriction, pericyte death, neutrophil stalling, and improved cerebrovascular reperfusion. Patch-clamp electrophysiology in pericytes, pharmacological TMEM16A inhibition, rodent middle cerebral artery occlusion stroke model, two-photon imaging of capillary diameter and pericyte Ca2+ The Journal of clinical investigation High 35316222
2022 TMEM16A interacts with GPX4 (glutathione peroxidase 4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis in hepatocytes; disruption of the TMEM16A-GPX4 interaction abrogates GPX4 ubiquitination and ferroptosis, and hepatocyte-specific TMEM16A knockout protects against hepatic ischemia/reperfusion injury. Co-immunoprecipitation, hepatocyte-specific knockout and overexpression mice, ubiquitination assays, disruption of protein-protein interaction, in vitro hypoxia/reoxygenation model, ferroptosis rescue experiments Cell death & disease High 36572666
2021 TMEM16A channel activity is promoted by ROCK1-mediated phosphorylation of moesin at T558; activated ROCK1 (downstream of RhoA/EGFR/STAT3) enhances TMEM16A Cl- currents via moesin phosphorylation, promoting breast cancer cell migration and invasion. Whole-cell patch clamp recordings, western blotting for moesin phosphorylation, ROCK1 inhibition, RhoA activation, transwell migration/invasion assays, mouse breast cancer lung metastasis model Journal of advanced research Medium 34603794
2018 TMEM16A is essential for basal mucus secretion in airways and intestine; airway-ciliated and intestinal epithelial cell-specific knockout of TMEM16A leads to accumulation of mucus in club cells and goblet cells respectively, and ATP-induced mucus secretion is abolished; TMEM16A mediates membrane exocytosis, while cholinergic compound exocytosis is TMEM16A-independent. Tissue-specific (FoxJ1 and Vil1) TMEM16A conditional knockout mice, ATP-induced mucus secretion assays, IL-8 release measurement, human Calu3 airway cell knockdown FASEB journal High 30586313
2023 ANO1, CaV1.2, and IP3R form a localized macromolecular complex at or near the plasma membrane of pulmonary arterial smooth muscle cells; pharmacological block or genetic ablation of ANO1 equally abolishes 5-HT-induced tone and intracellular Ca2+ waves as does CaV1.2 or IP3R inhibition, and co-immunoprecipitation confirms ANO1 pulls down both CaV1.2 and IP3R. Smooth muscle-specific ANO1 genetic ablation, co-immunoprecipitation, confocal and superresolution nanomicroscopy, patch-clamp, pharmacological inhibition, GCaMP Ca2+ imaging The Journal of general physiology High 37702787
2017 TMEM16A/ANO1 inhibits apoptosis in head and neck squamous cell carcinoma through downregulation of Bim expression, and correlates with increased Erk1/2 activity; loss of TMEM16A increases apoptotic activity and Bim levels in vitro and in vivo, contributing to cisplatin resistance. HNSCC cell culture, in vivo xenograft studies, western blotting for Bim and ERK1/2, immunostaining of human HNSCC samples, cisplatin resistance assays Clinical cancer research Medium 28899969
2023 Rare gain-of-function variants in ANO1 predispose to moyamoya disease; patch-clamp recordings of ANO1 variants from affected families demonstrate increased sensitivity to intracellular Ca2+, establishing a mechanism by which enhanced ANO1 activity causes cerebrovascular disease. Exome sequencing, haplotype analysis, patch-clamp electrophysiology of recombinant ANO1 variant channels in HEK cells Brain : a journal of neurology High 37253099
2019 SP1 transcriptionally activates ANO1 in gastric cancer by recruiting the histone methyltransferase MLL1 to the ANO1 promoter, facilitating H3K4 trimethylation and promoting ANO1 expression; ANO1 knockdown inhibits gastric cancer cell migration, invasion, and metastasis. Chromatin immunoprecipitation (ChIP), luciferase reporter assays, western blotting, in vitro migration/invasion assays, in vivo metastasis model Biochemical and biophysical research communications Medium 30871776
2019 TMEM16A overexpression promotes lysosomal biogenesis and exocytosis in a manner requiring reactive oxygen species, TRPML1, and activation of the β-catenin–MITF pathway, enabling sequestration and exocytosis of cisplatin and contributing to chemoresistance in squamous cell carcinoma of the head and neck. Genetic and pharmacological manipulation of TMEM16A, lysosomal biogenesis/exocytosis assays, cisplatin accumulation/efflux assays, TRPML1 and β-catenin/MITF pathway analysis, patient-derived xenograft model with hydroxychloroquine Proceedings of the National Academy of Sciences of the United States of America Medium 35286200
2023 ANO1 inhibits cancer ferroptosis through a PI3K-Akt signaling-dependent mechanism, promotes TGF-β release, facilitates cancer-associated fibroblast recruitment, and suppresses CD8+ T cell-mediated anti-tumor immunity, thereby conferring resistance to anti-PD-1 immunotherapy. ANO1 knockdown/inhibition, PI3K-Akt signaling analysis, TGF-β release assays, cancer-associated fibroblast recruitment assays, anti-PD-1 treatment in cell-derived and patient-derived xenograft models, multi-omics analysis Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 37341301
2016 LRRC8A (VRAC subunit) and ANO1/TMEM16A can be co-immunoprecipitated, and loss of LRRC8A expression attenuates Ca2+-activated Cl- currents while LRRC8A overexpression enhances them; ANO1 also promotes membrane capacitance increase and FM4-64 membrane binding upon Ca2+ elevation, suggesting a role in exocytosis. Co-immunoprecipitation, siRNA knockdown of LRRC8A, whole-cell patch clamp, membrane capacitance measurements, FM4-64 membrane binding assay Pflugers Archiv : European journal of physiology Medium 27514381
2015 TMEM16A activity is regulated by membrane phospholipids: PI(4,5)P2 is required for TMEM16A function (its depletion causes current decline independent of cytoskeleton), cholesterol modulates the channel directly and via PI(4,5)P2-independent mechanisms, and fatty acids (stearic, arachidonic, oleic, DHA, EPA) and phosphatidylserine inhibit TMEM16A in a dose- and voltage-dependent manner. Patch-clamp electrophysiology, PI(4,5)P2 depletion (rapamycin/iRap system), methyl-β-cyclodextrin cholesterol manipulation, exogenous fatty acid application, PI(4,5)P2 assay, fluorescence microscopy Biochimica et biophysica acta. Molecular and cell biology of lipids High 29277655

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. The American journal of pathology 475 15215166
2009 Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proceedings of the National Academy of Sciences of the United States of America 262 19965375
2012 TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression. Cancer research 259 22564524
2012 DOG1: a novel marker of salivary acinar and intercalated duct differentiation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 170 22460810
2011 Induction of dormancy in Arabidopsis summer annuals requires parallel regulation of DOG1 and hormone metabolism by low temperature and CBF transcription factors. The Plant cell 166 21803937
2018 Control of seed dormancy and germination by DOG1-AHG1 PP2C phosphatase complex via binding to heme. Nature communications 147 29875377
2016 DELAY OF GERMINATION1 (DOG1) regulates both seed dormancy and flowering time through microRNA pathways. Proceedings of the National Academy of Sciences of the United States of America 144 27035986
2012 Dynamic modulation of ANO1/TMEM16A HCO3(-) permeability by Ca2+/calmodulin. Proceedings of the National Academy of Sciences of the United States of America 138 23248295
2017 Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer. Molecular cancer 123 28893247
2017 MicroRNA-381 inhibits the metastasis of gastric cancer by targeting TMEM16A expression. Journal of experimental & clinical cancer research : CR 115 28193228
2022 The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia. The Journal of clinical investigation 106 35316222
2011 DOG1 expression is predicted by the seed-maturation environment and contributes to geographical variation in germination in Arabidopsis thaliana. Molecular ecology 106 21740475
2017 Epithelial Chloride Transport by CFTR Requires TMEM16A. Scientific reports 105 28963502
2014 Inhibition of TMEM16A expression suppresses growth and invasion in human colorectal cancer cells. PloS one 105 25541940
2019 The multifaceted role of TMEM16A in cancer. Cell calcium 103 31279157
2018 Recent advances in TMEM16A: Structure, function, and disease. Journal of cellular physiology 103 30515811
2015 Inhibition of Calcium-Activated Chloride Channel ANO1/TMEM16A Suppresses Tumor Growth and Invasion in Human Lung Cancer. PloS one 102 26305547
2010 Characterization of the oligomeric structure of the Ca(2+)-activated Cl- channel Ano1/TMEM16A. The Journal of biological chemistry 96 21056985
2015 Overexpression of ANO1/TMEM16A, an arterial Ca2+-activated Cl- channel, contributes to spontaneous hypertension. Journal of molecular and cellular cardiology 89 25739000
2018 TMEM16A is indispensable for basal mucus secretion in airways and intestine. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 84 30586313
2019 Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension. The European respiratory journal 77 31023847
2015 Seed Dormancy in Arabidopsis Is Controlled by Alternative Polyadenylation of DOG1. Plant physiology 73 26620523
2020 Delay of Germination-1 (DOG1): A Key to Understanding Seed Dormancy. Plants (Basel, Switzerland) 72 32283717
2020 The Ca2+-activated chloride channel ANO1/TMEM16A: An emerging therapeutic target for epithelium-originated diseases? Acta pharmaceutica Sinica. B 71 34221860
2015 9-Phenanthrol inhibits recombinant and arterial myocyte TMEM16A channels. British journal of pharmacology 71 25573456
2019 TMEM16A in Cystic Fibrosis: Activating or Inhibiting? Frontiers in pharmacology 70 30761000
2013 DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors. Cancer research 69 23576565
2020 Functional variants of DOG1 control seed chilling responses and variation in seasonal life-history strategies in Arabidopsis thaliana. Proceedings of the National Academy of Sciences of the United States of America 67 31964817
2018 Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-α signaling. Cell death & disease 63 29899325
2015 Seed Dormancy in Arabidopsis Requires Self-Binding Ability of DOG1 Protein and the Presence of Multiple Isoforms Generated by Alternative Splicing. PLoS genetics 63 26684465
2011 CFTR and TMEM16A are separate but functionally related Cl- channels. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 62 22178883
2022 Hepatocyte-specific TMEM16A deficiency alleviates hepatic ischemia/reperfusion injury via suppressing GPX4-mediated ferroptosis. Cell death & disease 61 36572666
2019 A network of phosphatidylinositol 4,5-bisphosphate binding sites regulates gating of the Ca2+-activated Cl- channel ANO1 (TMEM16A). Proceedings of the National Academy of Sciences of the United States of America 61 31515451
2014 Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte. American journal of physiology. Cell physiology 61 25298423
2010 The utility of discovered on gastrointestinal stromal tumor 1 (DOG1) antibody in surgical pathology-the GIST of it. Advances in anatomic pathology 61 20418677
2017 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 60 29277655
2014 Activation of Ca(2+) -activated Cl(-) channel ANO1 by localized Ca(2+) signals. The Journal of physiology 57 25398532
2020 Arctigenin, a novel TMEM16A inhibitor for lung adenocarcinoma therapy. Pharmacological research 53 32097750
2017 Antisense transcription represses Arabidopsis seed dormancy QTL DOG1 to regulate drought tolerance. EMBO reports 51 29030481
2014 Pharmacological characterization of TMEM16A currents. Channels (Austin, Tex.) 51 24642630
2014 Sinupret activates CFTR and TMEM16A-dependent transepithelial chloride transport and improves indicators of mucociliary clearance. PloS one 51 25117505
2017 TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression. Clinical cancer research : an official journal of the American Association for Cancer Research 49 28899969
2016 Local coupling of TRPC6 to ANO1/TMEM16A channels in smooth muscle cells amplifies vasoconstriction in cerebral arteries. American journal of physiology. Cell physiology 48 27147559
2014 Functional role of the Ca²⁺-activated Cl⁻ channel DOG1/TMEM16A in gastrointestinal stromal tumor cells. Experimental cell research 47 24825187
2010 Ectopic expression of wheat and barley DOG1-like genes promotes seed dormancy in Arabidopsis. Plant science : an international journal of experimental plant biology 47 21802612
2023 ANO1-Mediated Inhibition of Cancer Ferroptosis Confers Immunotherapeutic Resistance through Recruiting Cancer-Associated Fibroblasts. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 46 37341301
2019 Emerging Perspectives on Pain Management by Modulation of TRP Channels and ANO1. International journal of molecular sciences 45 31336748
2019 TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension. British journal of pharmacology 44 30710335
2019 The Evening Complex and the Chromatin-Remodeling Factor PICKLE Coordinately Control Seed Dormancy by Directly Repressing DOG1 in Arabidopsis. Plant communications 42 33404551
2018 TRPV4 heats up ANO1-dependent exocrine gland fluid secretion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 29187363
2019 Trait analysis reveals DOG1 determines initial depth of seed dormancy, but not changes during dormancy cycling that result in seedling emergence timing. The New phytologist 41 31359436
2017 TMEM16A/ANO1 suppression improves response to antibody-mediated targeted therapy of EGFR and HER2/ERBB2. Genes, chromosomes & cancer 39 28177558
2014 The Ca2+-activated Cl- channel ANO1/TMEM16A regulates primary ciliogenesis. Molecular biology of the cell 39 24694595
2009 Pancreatic expression of DOG1: a novel gastrointestinal stromal tumor (GIST) biomarker. Applied immunohistochemistry & molecular morphology : AIMM 39 19417627
2013 Control of TMEM16A by INO-4995 and other inositolphosphates. British journal of pharmacology 37 22946960
2021 Molecular mechanisms of activation and regulation of ANO1-Encoded Ca2+-Activated Cl- channels. Channels (Austin, Tex.) 36 34488544
2021 Cepharanthine, a novel selective ANO1 inhibitor with potential for lung adenocarcinoma therapy. Biochimica et biophysica acta. Molecular cell research 35 34450215
2021 Activation of TMEM16A Ca2+-activated Cl- channels by ROCK1/moesin promotes breast cancer metastasis. Journal of advanced research 35 34603794
2022 Nuciferine Inhibits TMEM16A in Dietary Adjuvant Therapy for Lung Cancer. Journal of agricultural and food chemistry 34 35298888
2022 TMEM16A as a potential treatment target for head and neck cancer. Journal of experimental & clinical cancer research : CR 34 35668455
2020 Calcium-Activated Chloride Channel ANO1/TMEM16A: Regulation of Expression and Signaling. Frontiers in physiology 34 33250781
2018 Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors. European journal of medicinal chemistry 34 30347323
2017 ANO1 inhibits cardiac fibrosis after myocardial infraction via TGF-β/smad3 pathway. Scientific reports 33 28539652
2021 Theaflavin binds to a druggable pocket of TMEM16A channel and inhibits lung adenocarcinoma cell viability. The Journal of biological chemistry 31 34329684
2021 TMEM16A, a Homoharringtonine Receptor, as a Potential Endogenic Target for Lung Cancer Treatment. International journal of molecular sciences 30 34681590
2017 The Mechanistic Role of the Calcium-Activated Chloride Channel ANO1 in Tumor Growth and Signaling. Advances in experimental medicine and biology 30 28293832
2022 Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy. Proceedings of the National Academy of Sciences of the United States of America 29 35286200
2021 The diverse roles of TMEM16A Ca2+-activated Cl- channels in inflammation. Journal of advanced research 29 34603778
2016 Relationship between TMEM16A/anoctamin 1 and LRRC8A. Pflugers Archiv : European journal of physiology 29 27514381
2020 ANO1 regulates cardiac fibrosis via ATI-mediated MAPK pathway. Cell calcium 28 33075549
2016 Revealing the activation pathway for TMEM16A chloride channels from macroscopic currents and kinetic models. Pflugers Archiv : European journal of physiology 28 27138167
2013 The seed dormancy defect of Arabidopsis mutants lacking the transcript elongation factor TFIIS is caused by reduced expression of the DOG1 gene. FEBS letters 28 24252221
2023 ANO1 Reprograms Cholesterol Metabolism and the Tumor Microenvironment to Promote Cancer Metastasis. Cancer research 27 36912612
2021 CLCA1 Regulates Airway Mucus Production and Ion Secretion Through TMEM16A. International journal of molecular sciences 27 34066250
2016 HCO3- Transport through Anoctamin/Transmembrane Protein ANO1/TMEM16A in Pancreatic Acinar Cells Regulates Luminal pH. The Journal of biological chemistry 26 27510033
2015 PKCα regulates TMEM16A-mediated Cl⁻ secretion in human biliary cells. American journal of physiology. Gastrointestinal and liver physiology 26 26542395
2014 The bestrophin- and TMEM16A-associated Ca(2+)- activated Cl(–) channels in vascular smooth muscles. Channels (Austin, Tex.) 26 25478625
2021 Diethylstilbestrol, a Novel ANO1 Inhibitor, Exerts an Anticancer Effect on Non-Small Cell Lung Cancer via Inhibition of ANO1. International journal of molecular sciences 24 34281152
2019 Transcriptional activation of ANO1 promotes gastric cancer progression. Biochemical and biophysical research communications 24 30871776
2016 Parallelism of DOG1 expression with recurrence risk in gastrointestinal stromal tumors bearing KIT or PDGFRA mutations. BMC cancer 24 26867653
2014 Functional swapping between transmembrane proteins TMEM16A and TMEM16F. The Journal of biological chemistry 24 24478309
2008 Mutation assay of the novel gene DOG1 in gastrointestinal stromal tumors (GISTs). Journal of gastroenterology 24 18648740
2023 Promoter-pervasive transcription causes RNA polymerase II pausing to boost DOG1 expression in response to salt. The EMBO journal 23 36705062
2019 Molecular mechanism of TMEM16A regulation: role of CaMKII and PP1/PP2A. American journal of physiology. Cell physiology 23 31461344
2016 New Insights on the Regulation of Ca2+ -Activated Chloride Channel TMEM16A. Journal of cellular physiology 23 27682822
2015 DOG1 is a sensitive and specific immunohistochemical marker for diagnosis of canine gastrointestinal stromal tumors. Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 23 25862711
2023 Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease. Brain : a journal of neurology 22 37253099
2019 Anoctamin 1/TMEM16A controls intestinal Cl- secretion induced by carbachol and cholera toxin. Experimental & molecular medicine 22 31383845
2017 Sox10 and DOG1 Expression in Primary Adnexal Tumors of the Skin. The American Journal of dermatopathology 21 28394798
2015 Diagnostic role of DOG1 and p63 immunohistochemistry in salivary gland carcinomas. International journal of clinical and experimental pathology 21 26464669
2013 Developmental expression of the calcium-activated chloride channels TMEM16A and TMEM16B in the mouse olfactory epithelium. Developmental neurobiology 21 24318978
2023 Inhibition of TMEM16A improves cisplatin-induced acute kidney injury via preventing DRP1-mediated mitochondrial fission. Acta pharmacologica Sinica 20 37402998
2020 Ca2+-activated Cl- channel TMEM16A inhibition by cholesterol promotes angiogenesis in endothelial cells. Journal of advanced research 20 33842002
2015 CLCA1 and TMEM16A: the link towards a potential cure for airway diseases. Expert review of respiratory medicine 20 26296094
2023 ANO1, CaV1.2, and IP3R form a localized unit of EC-coupling in mouse pulmonary arterial smooth muscle. The Journal of general physiology 19 37702787
2017 TMEM16A regulates portal vein smooth muscle cell proliferation in portal hypertension. Experimental and therapeutic medicine 18 29434696
2015 Calmodulin regulation of TMEM16A and 16B Ca(2+)-activated chloride channels. Channels (Austin, Tex.) 18 26083059
2019 Biochemical Inhibition of DOG1/TMEM16A Achieves Antitumoral Effects in Human Gastrointestinal Stromal Tumor Cells In Vitro. Anticancer research 17 31262867
2015 Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis. Balkan medical journal 17 26740899
2011 Expression of DOG1, PDGFRA, and p16 in Gastrointestinal Stromal Tumors. Gut and liver 17 21814597