Skip to main content
SpringerLink
Log in

TMEM16 Proteins (Anoctamins) in Epithelia

  • Chapter
  • First Online:
Ion Channels and Transporters of Epithelia in Health and Disease

Part of the book series: Physiology in Health and Disease ((PIHD))

  • 1471 Accesses

Abstract

The members of transmembrane 16 (TMEM16) family, also known as anoctamins, are membrane proteins characterized by eight putative transmembrane segments and regulated by cytosolic calcium. TMEM16A (ANO1) and TMEM16B (ANO2) are calcium-activated chloride channels, whereas other anoctamins, such as TMEM16F (ANO6), are associated with calcium-activated scrambling of membrane glycerophospholipids and sphingolipids. TMEM16F also shows ion channel activity although at very high calcium concentrations. In airway, salivary, biliary, and pancreatic epithelial cells, TMEM16A represents a route for chloride and bicarbonate secretion across the apical membrane. In airway epithelial cells, TMEM16A expression is strongly stimulated by Th2 cytokines IL-4 and IL-13. This upregulation occurs in mucus-producing goblet cells thus indicating a particular role of TMEM16A in mucus release and expansion. In intestinal epithelial cells, TMEM16A shows instead a basolateral localization and a different mechanism to modulate transepithelial ion transport.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Bolduc V, Marlow G, Boycott KM, Saleki K, Inoue H, Kroon J, Itakura M, Robitaille Y, Parent L, Baas F, Mizuta K, Kamata N, Richard I, Linssen WH, Mahjneh I, de Visser M, Bashir R, Brais B (2010) Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am J Hum Genet 86:213–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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:E1026–E1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buchholz B, Faria D, Schley G, Schreiber R, Eckardt KU, Kunzelmann K (2014) Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst–forming epithelial cells. Kidney Int 85:1058–1067

    Article  CAS  PubMed  Google Scholar 

  • Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ (2008) TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 322:590–594

    Article  CAS  PubMed  Google Scholar 

  • Curran DR, Cohn L (2010) Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am J Respir Cell Mol Biol 42:268–275

    Article  CAS  PubMed  Google Scholar 

  • Danahay H, Atherton H, Jones G, Bridges RJ, Poll CT (2002) Interleukin-13 induces a hypersecretory ion transport phenotype in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 282:L226–L236

    Article  CAS  PubMed  Google Scholar 

  • Dutta AK, Khimji AK, Kresge C, Bugde A, Dougherty M, Esser V, Ueno Y, Glaser SS, Alpini G, Rockey DC, Feranchak AP (2011) Identification and functional characterization of TMEM16A, a Ca2+-activated Cl- channel activated by extracellular nucleotides, in biliary epithelium. J Biol Chem 286:766–776

    Article  CAS  PubMed  Google Scholar 

  • Dutta AK, Woo K, Khimji AK, Kresge C, Feranchak AP (2013) Mechanosensitive Cl− secretion in biliary epithelium mediated through TMEM16A. Am J Physiol Gastrointest Liver Physiol 304:G87–G98

    Article  CAS  PubMed  Google Scholar 

  • Ehlen HW, Chinenkova M, Moser M, Munter HM, Krause Y, Gross S, Brachvogel B, Wuelling M, Kornak U, Vortkamp A (2013) Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues. J Bone Miner Res 28:246–259

    Article  CAS  PubMed  Google Scholar 

  • Fallah G, Römer T, Detro-Dassen S, Braam U, Markwardt F, Schmalzing G (2011) TMEM16A(a)/anoctamin-1 shares a homodimeric architecture with CLC chloride channels. Mol Cell Proteomics 10:1–10

    Article  Google Scholar 

  • Faria D, Rock JR, Romao AM, Schweda F, Bandulik S, Witzgall R, Schlatter E, Heitzmann D, Pavenstädt H, Herrmann E, Kunzelmann K, Schreiber R (2014) The calcium-activated chloride channel Anoctamin 1 contributes to the regulation of renal function. Kidney Int 85:1369–1381

    Article  CAS  PubMed  Google Scholar 

  • Ferrera L, Caputo A, Ubby I, Bussani E, Zegarra-Moran O, Ravazzolo R, Pagani F, Galietta LJ (2009) Regulation of TMEM16A chloride channel properties by alternative splicing. J Biol Chem 284:33360–33368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fischer H, Illek B, Sachs L, Finkbeiner WE, Widdicombe JH (2010) CFTR and calcium-activated chloride channels in primary cultures of human airway gland cells of serous or mucous phenotype. Am J Physiol Lung Cell Mol Physiol 299:L585–L594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galietta LJ, Pagesy P, Folli C, Caci E, Romio L, Costes B, Nicolis E, Cabrini G, Goossens M, Ravazzolo R, Zegarra-Moran O (2002) IL-4 is a potent modulator of ion transport in the human bronchial epithelium in vitro. J Immunol 168:839–845

    Article  CAS  PubMed  Google Scholar 

  • Garcia MA, Yang N, Quinton PM (2009) Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. J Clin Invest 119:2613–2622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grubb BR, Vick RN, Boucher RC (1994) Hyperabsorption of Na+ and raised Ca2+-mediated Cl- secretion in nasal epithelia of CF mice. Am J Physiol Cell Physiol 266:C1478–C1483

    CAS  Google Scholar 

  • Grubb S, Poulsen KA, Juul CA, Kyed T, Klausen TK, Larsen EH, Hoffmann EK (2013) TMEM16F (Anoctamin 6), an anion channel of delayed Ca2+ activation. J Gen Physiol 141:585–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE, Thorell K, Hebert H, Sjövall H, Hansson GC (2012) Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J Exp Med 209:1263–1272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He Q, Halm ST, Zhang J, Halm DR (2011) Activation of the basolateral membrane Cl− conductance essential for electrogenic K+ secretion suppresses electrogenic Cl− secretion. Exp Physiol 96:305–316

    Article  CAS  PubMed  Google Scholar 

  • Hoegger MJ, Fischer AJ, McMenimen JD, Ostedgaard LS, Tucker AJ, Awadalla MA, Moninger TO, Michalski AS, Hoffman EA, Zabner J, Stoltz DA, Welsh MJ (2014) Cystic fibrosis. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 345:818–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang F, Rock JR, Harfe BD, Cheng T, Huang X, Jan YN, Jan LY (2009) Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proc Natl Acad Sci U S A 106:21413–21418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD, Donne ML, Huang X, Sheppard D, Fahy JV, Wolters PJ, Hogan BL, Finkbeiner WE, Li M, Jan YN, Jan LY, Rock JR (2012) Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction. Proc Natl Acad Sci U S A 109:16354–16359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang F, Wang X, Ostertag EM, Nuwal T, Huang B, Jan YN, Basbaum AI, Jan LY (2013) TMEM16C facilitates Na+-activated K+ currents in rat sensory neurons and regulates pain processing. Nat Neurosci 16:1284–1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin X, Shah S, Liu Y, Zhang H, Lees M, Fu Z, Lippiat JD, Beech DJ, Sivaprasadarao A, Baldwin SA, Zhang H, Gamper N (2013) Activation of the Cl− channel ANO1 by localized calcium signals in nociceptive sensory neurons requires coupling with the IP3 receptor. Sci Signal 6:ra73

    Article  PubMed  PubMed Central  Google Scholar 

  • Jung J, Nam JH, Park HW, Oh U, Yoon JH, Lee MG (2013) Dynamic modulation of ANO1/TMEM16A HCO3 − permeability by Ca2+/calmodulin. Proc Natl Acad Sci U S A 110:360–365

    Article  CAS  PubMed  Google Scholar 

  • Lee RJ, Foskett JK (2010) Mechanisms of Ca2+-stimulated fluid secretion by porcine bronchial submucosal gland serous acinar cells. Am J Physiol Lung Cell Mol Physiol 298:L210–L231

    Article  CAS  PubMed  Google Scholar 

  • Malvezzi M, Chalat M, Janjusevic R, Picollo A, Terashima H, Menon AK, Accardi A (2013) Ca2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel. Nat Commun 4:2367

    Article  PubMed  PubMed Central  Google Scholar 

  • Matsui H, Randell SH, Peretti SW, Davis CW, Boucher RC (1998) Coordinated clearance of periciliary liquid and mucus from airway surfaces. J Clin Invest 102:1125–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Namkung W, Phuan PW, Verkman AS (2011a) TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. J Biol Chem 286:2365–2374

    Article  CAS  PubMed  Google Scholar 

  • Namkung W, Yao Z, Finkbeiner WE, Verkman AS (2011b) Small-molecule activators of TMEM16A, a calcium-activated chloride channel, stimulate epithelial chloride secretion and intestinal contraction. FASEB J 25:4048–4062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ousingsawat J, Martins JR, Schreiber R, Rock JR, Harfe BD, Kunzelmann K (2009) Loss of TMEM16A causes a defect in epithelial Ca2+-dependent chloride transport. J Biol Chem 284:28698–28703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park KS, Korfhagen TR, Bruno MD, Kitzmiller JA, Wan H, Wert SE, Khurana Hershey GK, Chen G, Whitsett JA (2007) SPDEF regulates goblet cell hyperplasia in the airway epithelium. J Clin Invest 117:978–988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedemonte N, Galietta LJ (2014) Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 94:419–459

    Article  CAS  PubMed  Google Scholar 

  • Perez-Cornejo P, Gokhale A, Duran C, Cui Y, Xiao Q, Hartzell HC, Faundez V (2012) Anoctamin 1 (Tmem16A) Ca2+-activated chloride channel stoichiometrically interacts with an ezrin-radixin-moesin network. Proc Natl Acad Sci U S A 109:10376–10381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pezzulo AA, Tang XX, Hoegger MJ, Alaiwa MH, Ramachandran S, Moninger TO, Karp PH, Wohlford-Lenane CL, Haagsman HP, van Eijk M, Bánfi B, Horswill AR, Stoltz DA, McCray PB Jr, Welsh MJ, Zabner J (2012) Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 487:109–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pifferi S, Dibattista M, Menini A (2009) TMEM16B induces chloride currents activated by calcium in mammalian cells. Pflugers Arch 458:1023–1038

    Article  CAS  PubMed  Google Scholar 

  • Qu Z, Yao W, Yao R, Liu X, Yu K, Hartzell C (2014) The Ca2+-activated Cl− channel, ANO1 (TMEM16A), is a double-edged sword in cell proliferation and tumorigenesis. Cancer Med 3:453–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riordan JR (2008) CFTR function and prospects for therapy. Annu Rev Biochem 77:701–726

    Article  CAS  PubMed  Google Scholar 

  • Rock JR, Futtner CR, Harfe BD (2008) The transmembrane protein TMEM16A is required for normal development of the murine trachea. Dev Biol 321:141–149

    Article  CAS  PubMed  Google Scholar 

  • Rock JR, O’Neal WK, Gabriel SE, Randell SH, Harfe BD, Boucher RC, Grubb BR (2009) Transmembrane protein 16A (TMEM16A) is a Ca2+-regulated Cl- secretory channel in mouse airways. J Biol Chem 284:14875–14880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Romanenko VG, Catalán MA, Brown DA, Putzier I, Hartzell HC, Marmorstein AD, Gonzalez-Begne M, Rock JR, Harfe BD, Melvin JE (2010) Tmem16A encodes the Ca2+-activated Cl− channel in mouse submandibular salivary gland acinar cells. J Biol Chem 285:12990–13001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sauter DR, Novak I, Pedersen SF, Larsen EH, Hoffmann EK (2015) ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC). Pflugers Arch 467(7):1495–1508

    Article  CAS  PubMed  Google Scholar 

  • Schreiber R, Uliyakina I, Kongsuphol P, Warth R, Mirza M, Martins JR, Kunzelmann K (2010) Expression and function of epithelial anoctamins. J Biol Chem 285:7838–7845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schreiber R, Faria D, Skryabin BV, Wanitchakool P, Rock JR, Kunzelmann K (2015) Anoctamins support calcium-dependent chloride secretion by facilitating calcium signaling in adult mouse intestine. Pflugers Arch 467(6):1203–1213

    Article  CAS  PubMed  Google Scholar 

  • Schroeder BC, Cheng T, Jan YN, Jan LY (2008) Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 134:1019–1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scudieri P, Caci E, Bruno S, Ferrera L, Schiavon M, Sondo E, Tomati V, Gianotti A, Zegarra-Moran O, Pedemonte N, Rea F, Ravazzolo R, Galietta LJ (2012) Association of TMEM16A chloride channel overexpression with airway goblet cell metaplasia. J Physiol 590:6141–6155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheridan JT, Worthington EN, Yu K, Gabriel SE, Hartzell HC, Tarran R (2011) Characterization of the oligomeric structure of the Ca2+-activated Cl− channel Ano1/TMEM16A. J Biol Chem 286:1381–1388

    Article  CAS  PubMed  Google Scholar 

  • Shimizu T, Iehara T, Sato K, Fujii T, Sakai H, Okada Y (2013) TMEM16F is a component of a Ca2+-activated Cl− channel but not a volume-sensitive outwardly rectifying Cl− channel. Am J Physiol Cell Physiol 304:C748–C759

    Article  CAS  PubMed  Google Scholar 

  • Stephan AB, Shum EY, Hirsh S, Cygnar KD, Reisert J, Zhao H (2009) ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification. Proc Natl Acad Sci U S A 106:11776–11781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stöhr H, Heisig JB, Benz PM, Schöberl S, Milenkovic VM, Strauss O, Aartsen WM, Wijnholds J, Weber BH, Schulz HL (2009) TMEM16B, a novel protein with calcium-dependent chloride channel activity, associates with a presynaptic protein complex in photoreceptor terminals. J Neurosci 29:6809–6818

    Article  PubMed  Google Scholar 

  • Sun H, Harris WT, Kortyka S, Kotha K, Ostmann AJ, Rezayat A, Sridharan A, Sanders Y, Naren AP, Clancy JP (2014) TGF-beta downregulation of distinct chloride channels in cystic fibrosis-affected epithelia. PLoS One 9, e106842

    Article  PubMed  PubMed Central  Google Scholar 

  • Suzuki J, Umeda M, Sims PJ, Nagata S (2010) Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468:834–838

    Article  CAS  PubMed  Google Scholar 

  • Suzuki J, Fujii T, Imao T, Ishihara K, Kuba H, Nagata S (2013) Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J Biol Chem 288:13305–13316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Svenningsen P, Nielsen MR, Marcussen N, Walter S, Jensen BL (2014) TMEM16A is a Ca2+-activated Cl− channel expressed in the renal collecting duct. Acta Physiol 212:166–174

    Article  CAS  Google Scholar 

  • Tian Y, Kongsuphol P, Hug M, Ousingsawat J, Witzgall R, Schreiber R, Kunzelmann K (2011) Calmodulin-dependent activation of the epithelial calcium-dependent chloride channel TMEM16A. FASEB J 25:1–11

    Article  Google Scholar 

  • Tien J, Lee HY, Minor DL Jr, Jan YN, Jan LY (2013) Identification of a dimerization domain in the TMEM16A calcium-activated chloride channel (CaCC). Proc Natl Acad Sci U S A 110:6352–6357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsutsumi S, Kamata N, Vokes TJ, Maruoka Y, Nakakuki K, Enomoto S, Omura K, Amagasa T, Nagayama M, Saito-Ohara F, Inazawa J, Moritani M, Yamaoka T, Inoue H, Itakura M (2004) The novel gene encoding a putative transmembrane protein is mutated in gnathodiaphyseal dysplasia (GDD). Am J Hum Genet 74:1255–1261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Haanes KA, Novak I (2013) Purinergic regulation of CFTR and Ca2+-activated Cl- channels and K+ channels in human pancreatic duct epithelium. Am J Physiol Cell Physiol 304:C673–C684

    Article  CAS  PubMed  Google Scholar 

  • Weiss HJ (1994) Scott syndrome: a disorder of platelet coagulant activity. Semin Hematol 31:312–319

    CAS  PubMed  Google Scholar 

  • Wolf W, Kilic A, Schrul B, Lorenz H, Schwappach B, Seedorf M (2012) Yeast Ist2 recruits the endoplasmic reticulum to the plasma membrane and creates a ribosome-free membrane microcompartment. PLoS One 7, e39703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao Q, Yu K, Perez-Cornejo P, Cui Y, Arreola J, Hartzell HC (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 108:8891–8896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U (2008) TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature 455:1210–1215

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Kim A, David T, Palmer D, Jin T, Tien J, Huang F, Cheng T, Coughlin SR, Jan YN, Jan LY (2012) TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation. Cell 151:111–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu K, Duran C, Qu Z, Cui YY, Hartzell HC (2012) Explaining calcium-dependent gating of anoctamin-1 chloride channels requires a revised topology. Circ Res 110:990–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu K, Zhu J, Qu Z, Cui YY, Hartzell HC (2014a) Activation of the Ano1 (TMEM16A) chloride channel by calcium is not mediated by calmodulin. J Gen Physiol 143:253–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Kuan AS, Chen TY (2014b) Calcium-calmodulin does not alter the anion permeability of the mouse TMEM16A calcium-activated chloride channel. J Gen Physiol 144:115–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Our work was supported by Ministero della Salute (Ricerca Finalizzata: GR-2009-1596824; Ricerca Corrente: Cinque per mille), Telethon Foundation (GGP10026), and Fondazione Italiana Fibrosi Cistica (FFC#2/2012).

Author information

Authors and Affiliations

  1. Istituto Giannina Gaslini, Genova, Italy

    Paolo Scudieri & Luis J. V. Galietta

Authors
  1. Paolo Scudieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis J. V. Galietta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luis J. V. Galietta .

Editor information

Editors and Affiliations

  1. Department of Physiology, University of Otago , Dunedin, Otago, New Zealand

    Kirk L. Hamilton

  2. Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Daniel C Devor

Rights and permissions

Reprints and permissions

Copyright information

© 2016 American Physiological Society

About this chapter

Cite this chapter

Scudieri, P., Galietta, L.J.V. (2016). TMEM16 Proteins (Anoctamins) in Epithelia. In: Hamilton, K., Devor, D. (eds) Ion Channels and Transporters of Epithelia in Health and Disease. Physiology in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3366-2_17

Download citation

Publish with us

Policies and ethics

Search

Navigation