ANO1

ANO1
Identifiers
Aliases ANO1, DOG1, ORAOV2, TAOS2, TMEM16A, anoctamin 1
External IDs MGI: 2142149 HomoloGene: 75079 GeneCards: ANO1
Targeted by Drug
DIDS, flufenamic acid, fluoxetine, mibefradil, niflumic acid[1]
Orthologs
Species Human Mouse
Entrez

55107

101772

Ensembl

ENSG00000131620

ENSMUSG00000031075

UniProt

Q5XXA6

Q8BHY3

RefSeq (mRNA)

NM_018043

NM_001242349
NM_178642

RefSeq (protein)

NP_060513.5

NP_001229278.1
NP_848757.4

Location (UCSC) Chr 11: 70.08 – 70.19 Mb Chr 7: 144.59 – 144.75 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

Anoctamin-1 (ANO1) also known as Transmembrane member 16A (TMEM16A) is a protein that, in humans, is encoded by the ANO1 gene.[4][5] Anoctamin-1 is a voltage-sensitive calcium-activated chloride channel that is expressed in smooth muscle and epithelial cells;[6] it is highly expressed in human interstitial cells of Cajal (ICC) throughout the gastrointestinal tract.[7] Changes in ANO1 channel activity directly/positively correlate with ICC activity.[7]

Function

ANO1 is a transmembrane protein that functions as a calcium-activated chloride channel.[8] Ca2+, Sr2+, and Ba2+ activate the channel.[9]

Structure

No atomic resolution structure of this channel has yet been obtained.[10] However, biochemical evidence suggests that the channel assembles as a dimer of two ANO1 polypeptide subunits.[11][12] 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.[13]

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.[7][14][6] ANO1 blockers like niflumic acid have been shown to block slow waves, which produce motility, in the human intestine.[7][14] ANO1-knockout mice fail to produce slow waves altogether.[7][14] Carbachol has been shown to markedly activate the channel;[7][14] in light of this, it's not surprising that secretory diarrhea is a Carbachol overdose symptom.[15] Crofelemer, an antidiarrhoeal, inhibits this channel.[16][17] Consequently, ANO1 activation is necessary for normal function of the ICC and its generated pacemaker activity in the smooth muscles of the intestine.[7][14]

Its overexpression was reported in esophageal squamous cell carcinoma and breast cancer progression.[18][19]

References

  1. ↑ "Drugs that physically interact with Anoctamin-1 view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ "Entrez Gene: anoctamin 1, calcium activated chloride channel".
  5. ↑ 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.
  6. 1 2 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.
  7. 1 2 3 4 5 6 7 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 3272164Freely accessible. PMID 22002868.
  8. ↑ 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.
  9. ↑ 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 3906059Freely accessible. PMID 24489780. Retrieved 6 March 2014.
  10. ↑ Pfam PF04547; PDB search for PF04547
  11. ↑ 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 3033684Freely accessible. PMID 20974900.
  12. ↑ 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 3020746Freely accessible. PMID 21056985.
  13. ↑ 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 3102354Freely accessible. PMID 21555582.
  14. 1 2 3 4 5 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 3208225Freely accessible. PMID 21768263.
  15. ↑ 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 1550933Freely accessible. PMID 16740173.
  16. ↑ 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.
  17. ↑ 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 2802429Freely accessible. PMID 19808995.
  18. ↑ 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.
  19. ↑ 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 3600458Freely accessible. PMID 23431153.

Further reading

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