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1.A.17.1.1
The plasma membrane Ca2 -activated chloride (IClCa) channel, TMEM16A (Anoctamin 1a; ANO1a) (Huang et al., 2012; Chen et al. 2011). The mouse orthologue (Q8BHY3), TMEM16A (956aas), is localized to the apical membranes of epithelia as well as intracellular membranes in many cell types. Knockout mice show diminished rhythmic contraction of gastric smooth muscle (Huang et al., 2009). ANO1 is also required for normal tracheal development (Ousingsawat et al., 2009). Expression is upregulated by epidermal growth factor (Mroz and Keely, 2012). Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids are inhibitors (Kumar et al., 2012). TMEM16A channels contribute to the myogenic response in cerebral arteries (Bulley et al., 2012). Membrane stretch activates arterial myocyte TMEM16A channels, leading to membrane depolarization and vasoconstriction. A local Ca2+   signal generated by nonselective cation channels stimulates TMEM16A channels to induce myogenic constriction (Bulley et al., 2012).  Ca2+/calmodulin activates bicarbonate (anion) transport (Jung et al. 2012).  The protein exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013).  TMSs 5-6 of the 8 TMSs may comprise parts of the pore-loop that controls Cl- conductance (Adomaviciene et al. 2013).  ANO1 confers IClCa in retinal neurons and acts as an intrinsic regulator of the presynaptic membrane potential during synaptic transmission (Jeon et al. 2013).  TMEM16A may be a primary driver of the "Grow" (tumor proliferation) or "Go" (metastasis) model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation (Shiwarski et al. 2014).  Regulation of TMEM16A/16B by Ca2+ is mediated by preassociated apo-calmodulin (Yang et al. 2014).as well asCaMKIIδ (Gui et al. 2015).  Because the Cl- channel is the only active ion-selective conductance with a reversal potential that lies within the dynamic range of spiral ganglion neurons (SGN) action potentials, developmental alteration of [Cl-], and hence the equilibrium potential for Cl- (ECl), transforms the pre- to the posthearing phenotype (Zhang et al. 2015).  Four basic residues involved in ion selectivity and pore blocker sensitivity have been identified (Peters et al. 2015).  Channel activity is required for mucus secretion induced by interleukin-13 (Lin et al. 2015; Zhang et al. 2015). May interact cooperatively with TrpV1 (TC# 1.A.4.2.1) to form a thermal sensor (Kanazawa and Matsumoto 2014). Inhibitors have been described (Boedtkjer et al. 2015).  The first intracellular loop serves as a Ca2+ binding site and includes D439, E444 and E447 (Pang et al. 2015).  Inhibited by various 4-Aryl-2-amino thiazoles at concentrations as low as 1 mμM (Piechowicz et al. 2016).  ANO1 and TRPC6 (1.A.4.1.5) are present in the same macromolecular complex and localize in close spatial proximity in the myocyte plasma membrane.  TRPC6 channels probably generate a local intracellular Ca2+ signal that activates nearby ANO1 channels in myocytes to stimulate vasoconstriction (Wang et al. 2016).  ANO1 transports bicarbonate which functions in the regulation of pancreatic acinar cell pH (Han et al. 2016).  TMEM16A contains two ion conduction pores that are independently activated by Ca2+ binding to sites that are embedded within the transmembrane part of each subunit (Lim et al. 2016).  Interactions between the carboxy- terminus and the first intracellular loop in the TMEM16A homo-dimer regulate channel activity (Scudieri et al. 2016).  A STAT6-TMEM16A-ERK1/2 signal pathway and TMEM16A channel activity are required for the Interleukin-13 (IL-13)-induced TMEM16A mediated mucus production (Qin et al. 2016). Angiotensin II elicits a TMEM16A-mediated current, and TMEM16A participates in Ang II-induced basilar constriction via the RhoA/ROCK signaling pathway (Li et al. 2016). 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) are inhibitors of TMEM16A, and 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa) have been synthesized and studied.  The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had an IC50 ~ 30 nM (Truong et al. 2017).  Plays a role in asthma (Wang et al. 2017).

Accession Number:Q5XXA6
Protein Name:Anoctamin-1
Length:986
Molecular Weight:114078.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:8
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate Cl-, bicarbonate

Cross database links:

Genevestigator: Q5XXA6
HEGENOM: HBG357842
RefSeq: NP_060513.5   
Entrez Gene ID: 55107   
Pfam: PF04547   
OMIM: 610108  gene
KEGG: hsa:55107   

Gene Ontology

GO:0034707 C:chloride channel complex
GO:0005737 C:cytoplasm
GO:0005886 C:plasma membrane
GO:0005229 F:intracellular calcium activated chloride ch...
GO:0006821 P:chloride transport

References (6)

[1] “Comprehensive genome and transcriptome analysis of the 11q13 amplicon in human oral cancer and synteny to the 7F5 amplicon in murine oral carcinoma.”  Huang X.et.al.   16906560
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[4] “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.”  Katoh M.et.al.   12739008
[5] “The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status.”  West R.B.et.al.   15215166
[6] “Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display.”  Carles A.et.al.   16261155

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FASTA formatted sequence
1:	MRVNEKYSTL PAEDRSVHII NICAIEDIGY LPSEGTLLNS LSVDPDAECK YGLYFRDGRR 
61:	KVDYILVYHH KRPSGNRTLV RRVQHSDTPS GARSVKQDHP LPGKGASLDA GSGEPPMDYH 
121:	EDDKRFRREE YEGNLLEAGL ELERDEDTKI HGVGFVKIHA PWNVLCREAE FLKLKMPTKK 
181:	MYHINETRGL LKKINSVLQK ITDPIQPKVA EHRPQTMKRL SYPFSREKQH LFDLSDKDSF 
241:	FDSKTRSTIV YEILKRTTCT KAKYSMGITS LLANGVYAAA YPLHDGDYNG ENVEFNDRKL 
301:	LYEEWARYGV FYKYQPIDLV RKYFGEKIGL YFAWLGVYTQ MLIPASIVGI IVFLYGCATM 
361:	DENIPSMEMC DQRHNITMCP LCDKTCSYWK MSSACATARA SHLFDNPATV FFSVFMALWA 
421:	ATFMEHWKRK QMRLNYRWDL TGFEEEEEAV KDHPRAEYEA RVLEKSLKKE SRNKEKRRHI 
481:	PEESTNKWKQ RVKTAMAGVK LTDKVKLTWR DRFPAYLTNL VSIIFMIAVT FAIVLGVIIY 
541:	RISMAAALAM NSSPSVRSNI RVTVTATAVI INLVVIILLD EVYGCIARWL TKIEVPKTEK 
601:	SFEERLIFKA FLLKFVNSYT PIFYVAFFKG RFVGRPGDYV YIFRSFRMEE CAPGGCLMEL 
661:	CIQLSIIMLG KQLIQNNLFE IGIPKMKKLI RYLKLKQQSP PDHEECVKRK QRYEVDYNLE 
721:	PFAGLTPEYM EMIIQFGFVT LFVASFPLAP LFALLNNIIE IRLDAKKFVT ELRRPVAVRA 
781:	KDIGIWYNIL RGIGKLAVII NAFVISFTSD FIPRLVYLYM YSKNGTMHGF VNHTLSSFNV 
841:	SDFQNGTAPN DPLDLGYEVQ ICRYKDYREP PWSENKYDIS KDFWAVLAAR LAFVIVFQNL 
901:	VMFMSDFVDW VIPDIPKDIS QQIHKEKVLM VELFMREEQD KQQLLETWME KERQKDEPPC 
961:	NHHNTKACPD SLGSPAPSHA YHGGVL