ANO1

Anoctamin 1, calcium activated chloride channel
Identifiers
Symbols	ANO1 ; DOG1; ORAOV2; TAOS2; TMEM16A
External IDs	OMIM: 610108 MGI: 2142149 HomoloGene: 75079 IUPHAR: 708 GeneCards: ANO1 Gene
Gene ontology Molecular function • calcium activated cation channel activity • intracellular calcium activated chloride channel activity • voltage-gated chloride channel activity • chloride channel activity • protein binding • iodide transmembrane transporter activity • protein homodimerization activity • protein heterodimerization activity Cellular component • cytoplasm • plasma membrane • external side of plasma membrane • apical plasma membrane • chloride channel complex • extracellular exosome Biological process • cation transport • chloride transport • phospholipase C-activating G-protein coupled receptor signaling pathway • multicellular organismal development • iodide transport • ion transmembrane transport • cellular response to heat • positive regulation of insulin secretion involved in cellular response to glucose stimulus • regulation of membrane potential • detection of temperature stimulus involved in sensory perception of pain • transmembrane transport • cation transmembrane transport • chloride transmembrane transport • regulation of anion transmembrane transport Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	55107	101772
Ensembl	ENSG00000131620	ENSMUSG00000031075
UniProt	Q5XXA6	Q8BHY3
RefSeq (mRNA)	NM_018043	NM_001242349
RefSeq (protein)	NP_060513	NP_001229278
Location (UCSC)	Chr 11: 70.08 – 70.19 Mb	Chr 7: 144.59 – 144.75 Mb
PubMed search

Anoctamin-1 (ANO1) also known as Transmembrane member 16A (TMEM16A) is a protein that, in humans, is encoded by the ANO1 gene.^[1][2] Anoctamin-1 is a voltage-sensitive calcium-activated chloride channel that is expressed in smooth muscle and epithelial cells;^[3] it is highly expressed in human interstitial cells of Cajal (ICC) throughout the gastrointestinal tract.^[4] Changes in ANO1 channel activity directly/positively correlate with ICC activity.^[4]

Function

ANO1 is a transmembrane protein that functions as a calcium-activated chloride channel.^[5] Ca²⁺, Sr²⁺, and Ba²⁺ activate the channel.^[6]

Structure

No atomic resolution structure of this channel has yet been obtained.^[7] However, biochemical evidence suggests that the channel assembles as a dimer of two ANO1 polypeptide subunits.^[8][9] From hydropathy plotting, each subunit is thought to encode a molecule with eight transmembrane domains, with a reentrant loop between the fifth and sixth transmembrane domains. The reentrant loop is thought to be a P loop-like structure responsible for the ion selectivity of the protein.^[10]

Clinical significance

ANO1 is expressed in the human gastrointestinal epithelium and is highly expressed in the gastrointestinal interstitial cells of Cajal, where it plays an important role in epithelial chloride secretion mediating intestinal motility.^[4][11][3] ANO1 blockers like niflumic acid have been shown to block slow waves, which produce motility, in the human intestine.^[4][11] ANO1-knockout mice fail to produce slow waves altogether.^[4][11] Carbachol has been shown to markedly activate the channel;^[4][11] in light of this, it's not surprising that secretory diarrhea is a Carbachol overdose symptom.^[12] Crofelemer, an antidiarrhoeal, inhibits this channel.^[13][14] Consequently, ANO1 activation is necessary for normal function of the ICC and its generated pacemaker activity in the smooth muscles of the intestine.^[4][11]

Its overexpression was reported in esophageal squamous cell carcinoma and breast cancer progression.^[15][16]

References

1. "Entrez Gene: anoctamin 1, calcium activated chloride channel".
2. Katoh M, Katoh M (June 2003). "FLJ10261 gene, located within the CCND1-EMS1 locus on human chromosome 11q13, encodes the eight-transmembrane protein homologous to C12orf3, C11orf25 and FLJ34272 gene products". Int. J. Oncol. 22 (6): 1375–81. doi:10.3892/ijo.22.6.1375. PMID 12739008.
3. Pedemonte N, Galietta LJ (2014). "Structure and function of TMEM16 proteins (anoctamins)". Physiol. Rev. 94 (2): 419–59. doi:10.1152/physrev.00039.2011. PMID 24692353.
4. Sanders KM, Zhu MH, Britton F, Koh SD, Ward SM (February 2012). "Anoctamins and gastrointestinal smooth muscle excitability". Exp. Physiol. 97 (2): 200–206. doi:10.1113/expphysiol.2011.058248. PMC 3272164. PMID 22002868.
5. Kunzelmann K, Tian Y, Martins JR, Faria D, Kongsuphol P, Ousingsawat J, Thevenod F, Roussa E, Rock J, Schreiber R (August 2011). "Anoctamins". Pflugers Arch. 462 (2): 195–208. doi:10.1007/s00424-011-0975-9. PMID 21607626.
6. Ni YL, Kuan AS, Chen TY (2014). "Activation and Inhibition of TMEM16A Calcium-Activated Chloride Channels". PLoS ONE 9 (1): e86734. doi:10.1371/journal.pone.0086734. PMC 3906059. PMID 24489780. Retrieved 6 March 2014.
7. Pfam PF04547; PDB search for PF04547
8. Fallah G, Römer T, Detro-Dassen S, Braam U, Markwardt F, Schmalzing G (February 2011). "TMEM16A(a)/anoctamin-1 Shares a Homodimeric Architecture with CLC Chloride Channels". Mol. Cell Proteomics 10 (2): M110.004697. doi:10.1074/mcp.M110.004697. PMC 3033684. PMID 20974900.
9. Sheridan JT, Worthington EN, Yu K, Gabriel SE, Hartzell HC, Tarran R (January 2011). "Characterization of the Oligomeric Structure of the Ca2+-activated Cl− Channel Ano1/TMEM16A". J. Biol. Chem. 286 (2): 1381–8. doi:10.1074/jbc.M110.174847. PMC 3020746. PMID 21056985.
10. Xiao Q, Yu K, Perez-Cornejo P, Cui Y, Arreola J, Hartzell HC (May 2011). "Voltage- and calcium-dependent gating of TMEM16A/Ano1 chloride channels are physically coupled by the first intracellular loop". Proc. Natl. Acad. Sci. U.S.A. 108 (21): 8891–6. doi:10.1073/pnas.1102147108. PMC 3102354. PMID 21555582.
11. Zhu MH, Sung IK, Zheng H, Sung TS, Britton FC, O'Driscoll K, Koh SD, Sanders KM (September 2011). "Muscarinic activation of Ca2+-activated Cl- current in interstitial cells of Cajal". J. Physiol. (Lond.) 589 (Pt 18): 4565–82. doi:10.1113/jphysiol.2011.211094. PMC 3208225. PMID 21768263.
12. Schulz M, Graefe T, Stuby K, Andresen H, Kupfermann N, Schmoldt A (2006). "Case report: acute unintentional carbachol intoxication". Crit Care 10 (3): R84. doi:10.1186/cc4937. PMC 1550933. PMID 16740173.
13. Biswal S (2014). "Crofelemer: In HIV Associated Diarrhea and Secretory Diarrhea - A Patent Perspective". Recent Pat Antiinfect Drug Discov 9 (2): 136–43. PMID 25851117.
14. Tradtrantip, L.; Namkung, W.; Verkman, A. S. (2009). "Crofelemer, an Antisecretory Antidiarrheal Proanthocyanidin Oligomer Extracted from Croton lechleri, Targets Two Distinct Intestinal Chloride Channels". Molecular Pharmacology 77 (1): 69–78. doi:10.1124/mol.109.061051. PMC 2802429. PMID 19808995.
15. Kashyap MK, Marimuthu A, Kishore CJ, Peri S, Keerthikumar S, Prasad TS, Mahmood R, Rao S, Ranganathan P, Sanjeeviah RC, Vijayakumar M, Kumar KV, Montgomery EA, Kumar RV, Pandey A (January 2009). "Genomewide mRNA profiling of esophageal squamous cell carcinoma for identification of cancer biomarkers". Cancer Biol. Ther. 8 (1): 36–46. doi:10.4161/cbt.8.1.7090. PMID 18981721.
16. Britschgi A, Bill A, Brinkhaus H, Rothwell C, Clay I, Duss S, Rebhan M, Raman P, Guy CT, Wetzel K, George E, Popa MO, Lilley S, Choudhury H, Gosling M, Wang L, Fitzgerald S, Borawski J, Baffoe J, Labow M, Gaither LA, Bentires-Alj M (2013). "Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling". Proc. Natl. Acad. Sci. U.S.A. 110 (11): E1026–34. doi:10.1073/pnas.1217072110. PMC 3600458. PMID 23431153.

Further reading

• Miwa S, Nakajima T, Murai Y; et al. (2008). "Mutation assay of the novel gene DOG1 in gastrointestinal stromal tumors (GISTs)". J. Gastroenterol. 43 (7): 531–7. doi:10.1007/s00535-008-2195-4. PMID 18648740.
• Ota T, Suzuki Y, Nishikawa T; et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Liegl B, Hornick JL, Corless CL, Fletcher CD (2009). "Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes". Am. J. Surg. Pathol. 33 (3): 437–46. doi:10.1097/PAS.0b013e318186b158. PMID 19011564.
• Strausberg RL, Feingold EA, Grouse LH; et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR; et al. (2009). "Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract". Am. J. Physiol. Gastrointest. Liver Physiol. 296 (6): G1370–81. doi:10.1152/ajpgi.00074.2009. PMC 2697941. PMID 19372102.
• Yang YD, Cho H, Koo JY; et al. (2008). "TMEM16A confers receptor-activated calcium-dependent chloride conductance". Nature 455 (7217): 1210–5. doi:10.1038/nature07313. PMID 18724360.
• Katoh M, Katoh M (2004). "Identification and characterization of TMEM16E and TMEM16F genes in silico". Int. J. Oncol. 24 (5): 1345–9. doi:10.3892/ijo.24.5.1345. PMID 15067359.
• Hartzell HC, Yu K, Xiao Q; et al. (2009). "Anoctamin/TMEM16 family members are Ca2+-activated Cl− channels". J. Physiol. (Lond.) 587 (Pt 10): 2127–39. doi:10.1113/jphysiol.2008.163709. PMC 2697287. PMID 19015192.