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FLASH GENE
Symbol ANO1 contributors: mct/pgu - updated : 22-01-2019
HGNC name anoctamin 1, calcium activated chloride channel
HGNC id 21625
Location 11q13.3      Physical location : 69.924.407 - 70.035.649
Synonym name
  • oral cancer overexpressed 2
  • tumor amplified and overexpressed sequence 2
  • transmembrane protein 16A
  • transmembrane protein 16A (eight membrane-spanning domains)
  • discovered on gastrointestinal stromal tumors protein 1
  • Synonym symbol(s) FLJ10261, TAOS2, ORAOV2, TMEM16A, DOG1
    DNA
    TYPE functioning gene
    STRUCTURE 110.99 kb     25 Exon(s)
    MAPPING cloned Y linked N status provisional
    Map the human TMEM16A gene was mapped to chromosome 11q13 by sequencing analysis cen - D11S4095 - D11S4136 - TMEM16A - D11S4139 - D11S4196 - qter
    Authors PMID: 12739008
    RNA
    TRANSCRIPTS type messenger
    text
  • two alternatively spliced isoforms exist, one with and one without exon 15
  • three alternative exons, 6b, 13, and 15, coding for segments of 22, 4, and 26 amino acids, respectively, which are differently spliced in human organs and regulates chloride channel properties (PMID: 19819874)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    25 - 4811 114 986 in mouse epithelial cells of pulmonary bronchioles, pancreatic acinar cells, acinar cells in submandibular gland, epithelial cells of kidney, in Leydig cells, submandibular glands and in all retinal cell layers 2008 18724360
    - - - - - - 2017 28336549
  • including exon 13
  • exon 13 encodes residues EAVK on its first intracellular loop
  • EAVK segment "c" sequence confers Ca2+-dependent changes to the kinetics
  • - - - - - - 2015 26359375
  • containing a novel exon-"exon 0" upstream of and in frame with exon 1
  • exhibited greater changes in current density but lesser changes in kinetics than Ano1(-0) in response to varying intracellular Ca(2+)
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessel   highly Homo sapiens
    Digestiveintestine     Homo sapiens
     salivary glandsubmandibular  highly Homo sapiens
    Endocrinepancreasislet of Langerhans  highly Homo sapiens
    Nervousbrainhindbraincerebellumcerebellar cortex  Homo sapiens
    Reproductivefemale systembreastmammary gland highly Homo sapiens
    Respiratoryrespiratory tract   highly Homo sapiens
     respiratory tracttrachea  highly Homo sapiens
    Urinarykidneytubulecollecting duct highly Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscular     Homo sapiens
    Muscularsmoothciliary muscle highly Homo sapiens
    Muscularsmoothmuscularis mucosa (tractus digestif)   Homo sapiens
    Muscularsmoothuterus  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    Digestiveenterocyte Homo sapiens
    Digestiveepithelial cell Homo sapiens
    NervousPurkinje cell Homo sapiens
    Respiratoryepithelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal region of TMEM16A seems to have a regulatory role
  • eight transmembrane domains with the N- and C-terminal tails facing the cytoplasm
  • multiple protein kinase A, protein kinase C, protein kinase G and casein kinase phosphorylation sitesat intracellular protein segments
  • multiple glycosylation sites in extracellular
  • segments
  • N- and C-terminal tails facing the cytoplasm
  • a tyrosine phosphorylation site
  • mono polymer homomer , dimer
    HOMOLOGY
    interspecies ortholog to Tmem16a, murine
    ortholog to Tmem16a, Rattus norvegicus
    ortholog to LOC561998, danio rerio
    ortholog to LOC451719, Pan troglodytes
    intraspecies homolog to TMEM16D
    homolog to TMEM16C
    homolog to TMEM16B
    Homologene
    FAMILY
  • calcium-activated chloride channels family, TMEM16 family
  • anoctamin family
  • CATEGORY transport channel
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    text
  • localized intracellularly, and only a small fraction appears in the cell membrane
  • located in the apical membranes of epithelial cells in exocrine glands and trachea
  • is localized at the apical and lateral membranes of polarized epithelia
  • ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree
  • basic FUNCTION
  • having an essential function expressed in the airway and foregut epithelia
  • being an intrinsic constituent of the calcium-dependent chloride channel
  • may also have a function during proliferation and apoptotic cell death
  • mediates a G-protein-coupled receptors-activated chloride current
  • confers Ca2+ activated Cl- conductance
  • role of ANO1 in cell proliferation is important for the progression of the cell cycle at the G1/S checkpoint
  • important factor for the control of mucociliary clearance in airways
  • important role for Ca2+-dependent Cl- transport in a number of epithelial tissues
  • required for rhythmic contraction of the stomach smooth muscle
  • might serve as the downstream effector of calcium release from internal stores, as well as calcium influx, and cause depolarization leading to further calcium influx and activation of voltage-gated ion channels that is likely to be crucial for smooth muscle functions in a wide range of tissues
  • predominant role in ATP-stimulated chlore secretion in biliary epithelium
  • functions as a calcium-activated chloride channel (CaCC)
  • minor contributor to total, time-integrated CaCC current in airway and intestinal epithelia
  • both CFTR and ANO1 are separate molecular entities that show functional and molecular interaction
  • associates with the signaling/scaffolding proteins ezrin, radixin, moesin, and RHOA, which link the plasma membrane to the cytoskeleton
  • performs important functions in nonepithelial tissues including pacemaker activity in the gut and regulation of vascular and airway smooth muscle tone
  • may play a role in organization of the actin cytoskeleton, and actin cytoskeleton and its associated regulatory proteins could be implicated in ANO1 function by modulating ANO1 channel gating, directing the trafficking ANO1 to the apical membrane, or assembling ANO1 into signaling networks
  • chloride channels in general and ANO1 in particular are involved in the regulation of proliferation
  • GPR39 might modulate gut motility via regulating ANO1 function in fibroblast-like cells (FLCs)
  • ANO6 is an essential component of a Ca(2+)-activated Cl(-) channel with a Ca(2+) sensitivity that is distinct from that of ANO1/ANO2 and that it is not related to volume-sensitive outwardly rectifying Cl(-) channel (VSOR) activity
  • ANO6 constitutes a Ca(2+)-activated anion channel or a pore-forming subunit of an anion channel with properties distinct from ANO1
  • association of ANO1 with other proteins, such as calmodulin, is not required for its function
  • ANO1 and ANO6 use a similar mechanism for sorting to plasma membrane and protein stabilization, but their functional domains significantly differ
  • ANO1/TMEM16A regulates primary ciliogenesis
  • is a Ca(2+) -activated Cl(-) channel expressed in the collecting ducts
  • is responsible for most of the iodide efflux across the apical membrane of thyroid cells
  • ANO1 and ANO2 regulate diverse processes including mucus secretion, neuronal excitability, smooth muscle contraction, olfactory signal transduction, and cell proliferation
  • role for ANO1 in shaping the plasma membrane during oogenesis, with broad implications for the regulation of microvilli in epithelia
  • ANO1 overexpression promotes cancer cell proliferation and migration
  • promotes cell proliferation and migration of tumor cells
  • ANO1 is responsible for basolateral Ca2+-dependent Cl- secretion in RPE, whereas ANO6 and ANO10 may have different functions, such as modulating Ca2+ signals
  • ANO1, and ANO2 are plasma membrane proteins with Ca2+-dependent Cl- channel function
  • is a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease
  • confers calcium-activated chloride channel activity which is of importance for various cellular functions in secretory epithelia and involved in secretion-dependent renal cyst growth
  • may be involved in ureteric bud branching and proper nephron endowment
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    text TMEM16A is a candidate Ca2+-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes
    PATHWAY
    metabolism
    signaling
    a component
  • crucial component of epithelial volume-regulated Cl- channels
  • specifically forms a homodimer
  • regulation of anion fluxes in insulin-producing cells may involve both SLC4A4 and ANO1
  • ANO1, ANO2 are subunits of Ca2+-activated Cl&
  • 8722; channel (CaCC)
  • functioned as a Ca2+-activated Cl- channel in endothelial cells
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacts with both large and small GTPases, calcium binding proteins, kinases, and lipid-modifying enzymes
  • CLCA1 stabilizes TMEM16A on the cell surface, thus increasing surface expression, which results in increased calcium-dependent chloride currents
  • directly bound with CYBB and reduced the degradation of CYBB through the proteasome-dependent degradation pathway
  • TRPV1 interacts with ANO1, also called TMEM16A, in primary sensory neurons and this interaction enhanced TRPV1-mediated pain sensation
  • cell & other
    REGULATION
    activated by intracellular Ca2+
    activated by ATP through an increase in intracellular Ca2+ and a Ca2+-independent mechanism engaging extracellular-regulated protein kinases (ERK1/2)
    Other activated through nucleotides binding P2 receptors on the apical membrane
    lipids and fatty acids regulate ANO1 channels through a membrane-delimited protein-lipid interaction
    COPB1 negatively regulates ANO1 surface expression
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   amplification    
    in various cancers
    constitutional     --low  
    causes a defect in epithelial Ca2+-dependent chloride transport
    tumoral     --over  
    in gastrointestinal stromal tumors
    constitutional     --over  
    epithelial expression is increased in asthmatics, particularly in secretory cells
    tumoral     --over  
    in several cancers including esophageal cancer
    tumoral     --over  
    in many cancers, including gastrointestinal stromal tumors, gastric cancer, head and neck squamous cell carcinoma (HNSCC), colon cancer, pancreatic ductal adenocarcinoma, and esophageal cancer
    constitutional       loss of function
    selective ANO1 inhibition can reduce pain sensation
    constitutional       loss of function
    resulted in reduced nephron number and, subsequently, albuminuria and tubular damage
    Susceptibility
    Variant & Polymorphism
    Candidate gene abundance of TMEM16A in tumours suggesting that tmem16A proteins participate in tumorigenesis
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    respiratoryCF (mucoviscidosis) 
    may provide the basis for novel pharmacological strategies for the treatment of cystic fibrosis, because Ca2+-dependent Cl- channels may be activated to compensate for defective CFTR Cl- channel function
    respiratoryCF (mucoviscidosis) 
    may provide the basis for novel pharmacological strategies for the treatment of cystic fibrosis, because Ca2+-dependent Cl- channels may be activated to compensate for defective CFTR Cl- channel function
    digestiveliver 
    may be a potential target to modulate bile formation in the treatment of cholestatic liver disorders
    respiratory  
    ANO1-CLCA4 blockers, including those identified here, may positively impact multiple causes of asthma symptoms
    respiratoryCF (mucoviscidosis) 
    pharmacological activation of TMEM16A offers a potential therapeutic strategy to reduce the inflammation of CF airway epithelia
    cancer  
    pharmacological inhibition of ANO1 induces apoptosis and cell cycle arrest at G1 phase in different types of epithelium-originated cancer cells
    cancerdigestive 
    is a potential drug target for treating metastatic colorectal carcinoma
    ANIMAL & CELL MODELS
    knockdown of mouse Ano1 markedly reduced native calcium-activated chloride currents as well as saliva production in mice