ANO1

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Anoctamin 1, calcium activated chloride channel
Identifiers
Symbols ANO1 ; DOG1; ORAOV2; TAOS2; TMEM16A
External IDs OMIM610108 MGI2142149 HomoloGene75079 IUPHAR: CaCC GeneCards: ANO1 Gene
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:
69.92 – 70.04 Mb
Chr 7:
144.59 – 144.75 Mb
PubMed search [1] [2]

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 highly expressed in human interstitial cells of Cajal (ICC) throughout the gastrointestinal tract.[3] Changes in ANO1 channel activity directly/positively correlate with ICC activity.[3]

Function[edit]

ANO1 is a transmembrane protein that functions as a calcium-activated chloride channel.[4] Ca2+, Sr2+, and Ba2+ activate the channel.[5]

Structure[edit]

No atomic resolution structure of this channel has yet been obtained.[6] However, biochemical evidence suggests that the channel assembles as a dimer of two ANO1 polypeptide subunits.[7][8] 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.[9]

Clinical significance[edit]

ANO1 is highly expressed in human gastrointestinal interstitial cells of Cajal and plays an important role in mediating intestinal motility.[3][10] ANO1 blockers like niflumic acid have been shown to block slow waves, which produce motility, in the human intestine.[3][10] ANO1-knockout mice fail to produce slow waves altogether.[3][10] Carbachol has been shown to markedly activate the channel;[3][10] in light of this, it's not surprising that explosive secretory diarrhea is a Carbachol overdose symptom.[11] Crofelemer, an antidiarrhoeal, inhibits this channel.[12] Consequently, ANO1 activation is necessary for normal function of the ICC and its generated pacemaker activity in the smooth muscles of the intestine.[3][10]

Its overexpression was reported in esophageal squamous cell carcinoma and breast cancer progression.[13][14]

References[edit]

  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. ^ a b c d e f g 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ Pfam PF04547; PDB search for PF04547
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ a b c d e 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. 
  11. ^ 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. 
  12. ^ 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.  edit
  13. ^ 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. 
  14. ^ 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[edit]