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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_018043 25 - 4811 NP_060513 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 isoform EAVK - - - - - - 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 ANO1 Ex0 - - - - - - 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)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       highly Homo sapiens Digestive gallbladder       highly Homo sapiens   salivary gland submandibular     highly Homo sapiens Endocrine pancreas islet of Langerhans     highly Homo sapiens Nervous brain hindbrain cerebellum cerebellar cortex   Homo sapiens Reproductive female system breast mammary gland   highly Homo sapiens Respiratory respiratory tract       highly Homo sapiens   respiratory tract trachea     highly Homo sapiens Urinary kidney tubule collecting duct   highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular         Homo sapiens Muscular smooth ciliary muscle   highly Homo sapiens Muscular smooth muscularis mucosa (tractus digestif)     Homo sapiens Muscular smooth uterus

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Homo sapiens Digestive enterocyte Homo sapiens Digestive epithelial cell Homo sapiens Nervous Purkinje cell Homo sapiens Respiratory epithelial 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
	ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract, regulating gastrointestinal motility

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed respiratory CF (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 respiratory CF (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 digestive liver   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 respiratory CF (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 cancer digestive   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