Nucleotide Release by Airway Epithelia

  • Eduardo R. Lazarowski
  • Juliana I. Sesma
  • Lucia Seminario
  • Charles R. EstherJr.
  • Silvia M. Kreda
Chapter
Part of the Subcellular Biochemistry book series (SCBI, volume 55)

Abstract

The purinergic events regulating the airways’ innate defenses are initiated by the release of purines from the epithelium, which occurs constitutively and is enhanced by chemical or mechanical stimulation. While the external triggers have been reviewed exhaustively, this chapter focuses on current knowledge of the receptors and signaling cascades mediating nucleotide release. The list of secreted purines now includes ATP, ADP, AMP and nucleotide sugars, and involves at least three distinct mechanisms reflecting the complexity of airway epithelia. First, the constitutive mechanism involves ATP translocation to the ER/Golgi complex as energy source for protein folding, and fusion of Golgi-derived vesicles with the plasma membrane. Second, goblet cells package ATP with mucins into granules, which are discharged in response to P2Y2R activation and Ca2+-dependent signaling pathways. Finally, non-mucous cells support a regulated mechanism of ATP release involving protease activated receptor (PAR)-elicited G12/13 activation, leading to the RhoGEF-mediated exchange of GDP for GTP on RhoA, and cytoskeleton rearrangement. Together, these pathways provide fine tuning of epithelial responses regulated by purinergic signaling events.

Keywords

ATP release Airway epithelia Ectonucleotidase Thrombin Mucin 

References

  1. 1.
    Burnstock G (2006) Purinergic signaling-an overview. Novartis Found Symp 276:26–48PubMedCrossRefGoogle Scholar
  2. 2.
    von Kügelgen I (2006) Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol Ther 110:415–432CrossRefGoogle Scholar
  3. 3.
    Surprenant A, North RA (2009) Signaling at purinergic P2X receptors. Annu Rev Physiol 71:333–359PubMedCrossRefGoogle Scholar
  4. 4.
    Fredholm BB (2010) Adenosine receptors as drug targets. Exp Cell Res 316:1284–1288PubMedCrossRefGoogle Scholar
  5. 5.
    Ciruela F, Albergaria C, Soriano A, Cuffí L, Carbonell L, Sánchez S, Gandía J, Fernández-Dueñas V (2010) Adenosine receptors interacting proteins (ARIPs): behind the biology of adenosine signaling. Biochim Biophys Acta 1798:9–20PubMedCrossRefGoogle Scholar
  6. 6.
    Trincavelli ML, Daniele S, Martini C (2010) Adenosine receptors: what we know and what we are learning. Curr Top Med Chem 10:860–877PubMedCrossRefGoogle Scholar
  7. 7.
    Lazarowski ER, Boucher RC (2009) Purinergic receptors in airway epithelia. Curr Opin Pharmacol 9:262–267PubMedCrossRefGoogle Scholar
  8. 8.
    Davis CW, Dickey BF (2008) Regulated airway goblet cell mucin secretion. Annu Rev Physiol 70:487–512PubMedCrossRefGoogle Scholar
  9. 9.
    Morse DM, Smullen JL, Davis CW (2001) Differential effects of UTP, ATP, and adenosine on ciliary activity of human nasal epithelial cells. Am J Physiol 280:C1485–C1497Google Scholar
  10. 10.
    Jia Y, Mathews CJ, Hanrahan JW (1997) Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A. J Biol Chem 272:4978–4984PubMedCrossRefGoogle Scholar
  11. 11.
    Devor DC, Pilewski JM (1999) UTP inhibits Na+ absorption in wild-type and Delta F508 CFTR-expressing human bronchial epithelia. Am J Physiol 276:C827–C837PubMedGoogle Scholar
  12. 12.
    Yue G, Malik B, Yue G, Eaton DC (2002) Phosphatidylinositol 4, 5-bisphosphate (PIP2) stimulates epithelial sodium channel activity in A6 cells. J Biol Chem 277:11965–11969PubMedCrossRefGoogle Scholar
  13. 13.
    Ma HP, Saxena S, Warnock DG (2002) Anionic phospholipids regulate native and expressed epithelial sodium channel (ENaC). J Biol Chem 277:7641–7644PubMedCrossRefGoogle Scholar
  14. 14.
    Kunzelmann K, Bachhuber T, Regeer R, Markovich D, Sun J, Schreiber R (2005) Purinergic inhibition of the epithelial Na+ transport via hydrolysis of PIP2. FASEB J 19:142–143PubMedGoogle Scholar
  15. 15.
    Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJV (2008) TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 322:590–594PubMedCrossRefGoogle Scholar
  16. 16.
    Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim W-S, Park SP, Lee J, Lee B, Kim B-M, Raouf R, Shin YK, Oh U (2008) TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature 455:1210–1215PubMedCrossRefGoogle Scholar
  17. 17.
    Schroeder BC, Cheng T, Jan YN, Jan LY (2008) Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 134:1019–1029PubMedCrossRefGoogle Scholar
  18. 18.
    Lazarowski ER, Paradiso AM, Watt WC, Harden TK, Boucher RC (1997) UDP activates a mucosal-restricted receptor on human nasal epithelial cells that is distinct from the P2Y2 receptor. Proc Natl Acad Sci USA 94:2599–2603PubMedCrossRefGoogle Scholar
  19. 19.
    Muller T, Bayer H, Myrtek D, Ferrari D, Sorichter S, Ziegenhagen MW, Zissel G, Virchow JC Jr, Luttmann W, Norgauer J, Di Virgilio F, Idzko M (2005) The P2Y14 receptor of airway epithelial cells: coupling to intracellular Ca2+ and IL-8 secretion. Am J Respir Cell Mol Biol 33:601–609PubMedCrossRefGoogle Scholar
  20. 20.
    Barth K, Kasper M (2009) Membrane compartments and purinergic signaling: occurrence and function of P2X receptors in lung. FEBS J 276:341–353PubMedCrossRefGoogle Scholar
  21. 21.
    Taylor AL, Schwiebert LM, Smith JJ, King C, Jones JR, Sorscher EJ, Schwiebert EM (1999) Epithelial P2X purinergic receptor channel expression and function. J Clin Invest 104:875–884PubMedCrossRefGoogle Scholar
  22. 22.
    Ma W, Korngreen A, Weil S, Cohen EB, Priel A, Kuzin L, Silberberg SD (2006) Pore properties and pharmacological features of the P2X receptor channel in airway ciliated cells. J Physiol 571:503–517PubMedCrossRefGoogle Scholar
  23. 23.
    North RA, Surprenant A (2000) Pharmacology of cloned P2X receptors. Annu Rev Pharmacol Toxicol 40:563–580PubMedCrossRefGoogle Scholar
  24. 24.
    Rettinger J, Schmalzing G (2003) Activation and desensitization of the recombinant P2X1 receptor at nanomolar ATP concentrations. J Gen Physiol 121:451–461PubMedCrossRefGoogle Scholar
  25. 25.
    Rettinger J, Schmalzing G (2004) Desensitization masks nanomolar potency of ATP for the P2X1 receptor. J Biol Chem 279:6426–6433PubMedCrossRefGoogle Scholar
  26. 26.
    Guo C, Masin M, Qureshi OS, Murrell-Lagnado RD (2007) Evidence for functional P2X4/P2X7 heteromeric receptors. Mol Pharmacol 72:1447–1456PubMedCrossRefGoogle Scholar
  27. 27.
    North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067PubMedGoogle Scholar
  28. 28.
    Boucher RC (2002) An overview of the pathogenesis of cystic fibrosis lung disease. Adv Drug Deliv Rev 54:1359–1371PubMedCrossRefGoogle Scholar
  29. 29.
    Allen-Gipson DS, Wong J, Spurzem JR, Sisson JH, Wyatt TA (2006) Adenosine A2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells. Am J Physiol 290:L849–L855Google Scholar
  30. 30.
    Allen-Gipson DS, Spurzem K, Kolm N, Spurzem JR, Wyatt TA (2007) Adenosine promotion of cellular migration in bronchial epithelial cells is mediated by the activation of cyclic adenosine monophosphate-dependent protein kinase A. J Investig Med 55:378–385PubMedCrossRefGoogle Scholar
  31. 31.
    Morello S, Ito K, Yamamura S, Lee K-Y, Jazrawi E, DeSouza P, Barnes P, Cicala C, Adcock IM (2006) IL-1β and TNFα regulation of the adenosine receptor (A2A) expression: differential requirement for NFkB binding to the proximal promoter. J Immunol 177:7173–7183PubMedGoogle Scholar
  32. 32.
    Sun Y, Wu F, Sun F, Huang P (2008) Adenosine promotes IL-6 release in airway epithelia. J Immunol 180:4173–4181PubMedGoogle Scholar
  33. 33.
    Lazarowski ER, Tarran R, Grubb BR, van Heusden CA, Okada S, Boucher RC (2004) Nucleotide release provides a mechanism for airway surface liquid homeostasis. J Biol Chem 279:36855–36864PubMedCrossRefGoogle Scholar
  34. 34.
    Okada SF, Nicholas RA, Kreda SM, Lazarowski ER, Boucher RC (2006) Physiological regulation of ATP release at the apical surface of human airway epithelia. J Biol Chem 281:22992–23002PubMedCrossRefGoogle Scholar
  35. 35.
    Donaldson SH, Lazarowski ER, Picher M, Knowles MR, Stutts MJ, Boucher RC (2000) Basal nucleotide levels, release, and metabolism in normal and cystic fibrosis airways. Mol Med 6:969–982PubMedGoogle Scholar
  36. 36.
    Button B, Boucher RC (2008) Role of mechanical stress in regulating airway surface hydration and mucus clearance rates. Respir Physiol Neurobiol 163:189–201PubMedCrossRefGoogle Scholar
  37. 37.
    Tarran R, Button B, Picher M, Paradiso AM, Ribeiro CMP, Lazarowski ER, Zhang L, Collins PL, Pickles RJ, Fredburg JJ, Boucher RC (2005) Normal and cystic fibrosis airway surface liquid homeostasis: the effects of phasic shear stress and viral infections. J Biol Chem 280:35751–35759PubMedCrossRefGoogle Scholar
  38. 38.
    Tarran R, Trout L, Donaldson SH, Boucher RC (2006) Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. J Gen Physiol 127:591–604PubMedCrossRefGoogle Scholar
  39. 39.
    Button B, Picher M, Boucher RC (2007) Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia. J Physiol 580:577–592PubMedCrossRefGoogle Scholar
  40. 40.
    Zhong X, Malhotra R, Guidotti G (2003) ATP uptake in the Golgi and extracellular release require Mcd4 protein and the vacuolar H+-ATPase. J Biol Chem 278:33436–33444PubMedCrossRefGoogle Scholar
  41. 41.
    Esther CRJ, Sesma JI, Dohlman HG, Ault AD, Clas ML, Lazarowski ER, Boucher RC (2008) Similarities between UDP-glucose and adenine nucleotide release in yeast: involvement of the secretory pathway. Biochemistry 47:9269–9278PubMedCrossRefGoogle Scholar
  42. 42.
    Chambers JK, Macdonald LE, Sarau HM, Ames RS, Freeman K, Foley JJ, Zhu Y, McLaughlin MM, Murdock P, McMillan L, Trill J, Swift A, Aiyar N, Taylor P, Vawter L, Naheed S, Szekeres P, Hervieu G, Scott C, Watson JM, Murphy AJ, Duzic E, Klein C, Bergsma DJ, Wilson SJ, Livi GP (2000) A G protein-coupled receptor for UDP-glucose. J Biol Chem 275:10767–10771PubMedCrossRefGoogle Scholar
  43. 43.
    Lazarowski ER, Shea DA, Boucher RC, Harden TK (2003) Release of cellular UDP-glucose as a potential extracellular signaling molecule. Mol Pharmacol 63:1190–1197PubMedCrossRefGoogle Scholar
  44. 44.
    Kreda SM, Okada SF, van Heusden CA, O’Neal W, Gabriel S, Abdullah L, Davis CW, Boucher RC, Lazarowski ER (2007) Coordinated release of nucleotides and mucin from human airway epithelial Calu-3 cells. J Physiol 584:245–259PubMedCrossRefGoogle Scholar
  45. 45.
    Sesma JI, Esther CRJ, Kreda SM, Jones L, O’Neal WK, Nishihara S, Nicholas RA, Lazarowski E (2009) Endoplasmic reticulum/Golgi nucleotide sugar transporters contribute to the cellular release of UDP-sugar signaling molecules. J Biol Chem 284:12572–12583PubMedCrossRefGoogle Scholar
  46. 46.
    Perez M, Hirschberg CB (1986) Topography of glycosylation reactions in the rough endoplasmic reticulum membrane. J Biol Chem 261:6822–6830PubMedGoogle Scholar
  47. 47.
    Parodi AJ (2000) Protein glucosylation and its role in protein folding. Annu Rev Biochem 69:69–93PubMedCrossRefGoogle Scholar
  48. 48.
    Berninsone PM, Hirschberg CB (2000) Nucleotide sugar transporters of the Golgi apparatus. Curr Opin Struct Biol 10:542–547PubMedCrossRefGoogle Scholar
  49. 49.
    Ishida N, Kawakita M (2004) Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflügers Arch 447:768–775PubMedCrossRefGoogle Scholar
  50. 50.
    Suda T, Kamiyama S, Suzuki M, Kikuchi N, Nakayama K, Narimatsu H, Jigami Y, Aoki T, Nishihara S (2004) Molecular cloning and characterization of a human multisubstrate specific nucleotide-sugar transporter homologous to Drosophila fringe connection. J Biol Chem 279:26469–26474PubMedCrossRefGoogle Scholar
  51. 51.
    Ishida N, Kuba T, Aoki K, Miyatake S, Kawakita M, Sanai Y (2005) Identification and characterization of human Golgi nucleotide sugar transporter SLC35D2, a novel member of the SLC35 nucleotide sugar transporter family. Genomics 85:106–116PubMedCrossRefGoogle Scholar
  52. 52.
    Guillén E, Hirschberg CB (1995) Transport of adenosine triphosphate into endoplasmic reticulum proteoliposomes. Biochemistry 34:5472–5476PubMedCrossRefGoogle Scholar
  53. 53.
    Hirschberg CB, Robbins PW, Abeijon C (1998) Transporters of nucleotide sugars, ATP, and nucleotide sulfate in the endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem 67:49–69PubMedCrossRefGoogle Scholar
  54. 54.
    Bankston LA, Guidotti G (1996) Characterization of ATP transport into chromaffin granule ghosts: synergy of ATP and serotonin accumulation in chromaffin granule ghosts. J Biol Chem 271:17132–17138PubMedCrossRefGoogle Scholar
  55. 55.
    Scrivens M, Dickenson JM (2005) Functional expression of the P2Y14 receptor in murine T-lymphocytes. Br J Pharmacol 146:435–444PubMedCrossRefGoogle Scholar
  56. 56.
    Scrivens M, Dickenson JM (2006) Functional expression of the P2Y14 receptor in human neutrophils. Eur J Pharmacol 543:166–173PubMedCrossRefGoogle Scholar
  57. 57.
    Fricks IP, Carter RL, Lazarowski ER, Harden TK (2009) Gi-dependent cell signaling responses of the human P2Y14 receptor in model cell systems. J Pharmacol Exp Ther 330:162–168PubMedCrossRefGoogle Scholar
  58. 58.
    Boudreault F, Grygorczyk R (2004) Cell swelling-induced ATP release is tightly dependent on intracellular calcium elevations. J Physiol 561:499–513PubMedCrossRefGoogle Scholar
  59. 59.
    Tatur S, Groulx N, Orlov SN, Grygorczyk R (2007) Ca2+-dependent ATP release from A549 cells involves synergistic autocrine stimulation by coreleased uridine nucleotides. J Physiol 584:419–435PubMedCrossRefGoogle Scholar
  60. 60.
    Tatur S, Kreda S, Lazarowski E, Grygorczyk R (2008) Calcium-dependent release of adenosine and uridine nucleotides from A549 cells. Purinergic Signal 4:139–146PubMedCrossRefGoogle Scholar
  61. 61.
    Seminario-Vidal L, Kreda S, Jones L, O’Neal W, Trejo J, Boucher RC, Lazarowski ER (2009) Thrombin promotes release of ATP from lung epithelial cells through coordinated activation of Rho- and Ca2+-dependent signaling pathways. J Biol Chem 284:20638–20648PubMedCrossRefGoogle Scholar
  62. 62.
    Joseph SM, Buchakjian MR, Dubyak GR (2003) Colocalization of ATP release sites and ecto-ATPase activity at the extracellular surface of human astrocytes. J Biol Chem 278:23331–23342PubMedCrossRefGoogle Scholar
  63. 63.
    Kreda SM, Seminario-Vidal L, Heusden C, Lazarowski E (2008) Thrombin-promoted release of UDP-glucose from human astrocytoma cells. Br J Pharmacol 153:1528–1537PubMedCrossRefGoogle Scholar
  64. 64.
    Blum AE, Joseph SM, Przybylski RJ, Dubyak GR (2008) Rho-family GTPases modulate Ca2+-dependent ATP release from astrocytes. Am J Physiol 295:C231–C241CrossRefGoogle Scholar
  65. 65.
    Hirakawa M, Oike M, Karashima Y, Ito Y (2004) Sequential activation of RhoA and FAK/paxillin leads to ATP release and actin reorganization in human endothelium. J Physiol 558:479–488PubMedCrossRefGoogle Scholar
  66. 66.
    Asokananthan N, Graham PT, Fink J, Knight DA, Bakker AJ, McWilliam AS, Thompson PJ, Stewart GA (2002) Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells. J Immunol 168:3577–3585PubMedGoogle Scholar
  67. 67.
    Hains MD, Siderovski DP, Harden TK (2004) Application of RGS box proteins to evaluate G-protein selectivity in receptor-promoted signaling. Methods Enzymol 389:71–88PubMedCrossRefGoogle Scholar
  68. 68.
    Scemes E, Suadicani SO, Dahl G, Spray DC (2007) Connexin and pannexin mediated cell-cell communication. Neuron Glia Biol 3:199–208PubMedCrossRefGoogle Scholar
  69. 69.
    Boassa D, Qiu F, Dahl G, Sosinsky G (2008) Trafficking dynamics of glycosylated pannexin 1 proteins. Cell Commun Adhes 15:119–132PubMedCrossRefGoogle Scholar
  70. 70.
    Dahl G, Locovei S (2006) Pannexin: to gap or not to gap, is that a question? IUBMB Life 58:409–419PubMedCrossRefGoogle Scholar
  71. 71.
    Goodenough DA, Paul DL (2003) Beyond the gap: functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4:285–294PubMedCrossRefGoogle Scholar
  72. 72.
    Müller DJ, Hand GM, Engel A, Sosinsky GE (2002) Conformational changes in surface structures of isolated connexin 26 gap junctions. EMBO J 21:3598–3607PubMedCrossRefGoogle Scholar
  73. 73.
    Shestopalov VI, Panchin Y (2008) Pannexins and gap junction protein diversity. Cell Mol Life Sci 65:376–394PubMedCrossRefGoogle Scholar
  74. 74.
    Gómez-Hernández JM, de Miguel MP, Larrosa B, González D, Barrio LC (2003) Molecular basis of calcium regulation in connexin-32 hemichannels. Proc Natl Acad Sci USA 100:16030–16035PubMedCrossRefGoogle Scholar
  75. 75.
    Stout CE, Costantin JL, Naus CC, Charles AC (2002) Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277:10482–10488PubMedCrossRefGoogle Scholar
  76. 76.
    De Vuyst E, Decrock E, Cabooter L, Dubyak GR, Naus CC, Evans WH, Leybaert L (2006) Intracellular calcium changes trigger connexin 32 hemichannel opening. EMBO J 25:34–44PubMedCrossRefGoogle Scholar
  77. 77.
    Bruzzone R, Barbe MT, Jakob NJ, Monyer H (2005) Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytes. J Neurochem 92:1033–1043PubMedCrossRefGoogle Scholar
  78. 78.
    Dubyak GR (2009) Both sides now: multiple interactions of ATP with pannexin-1 hemichannels. Focus on “A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP”. Am J Physiol 296:C235–C241CrossRefGoogle Scholar
  79. 79.
    Ransford GA, Fregien N, Qiu F, Dahl G, Conner GE, Salathe M (2009) Pannexin 1 contributes to ATP release in airway epithelia. Am J Respir Cell Mol Biol 41:525–534PubMedCrossRefGoogle Scholar
  80. 80.
    Locovei S, Wang J, Dahl G (2006) Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett 580:239–244PubMedCrossRefGoogle Scholar
  81. 81.
    Mason SJ, Paradiso AM, Boucher RC (1991) Regulation of transepithelial ion transport and intracellular calcium by extracellular ATP in human normal and cystic fibrosis airway epithelium. Br J Pharmacol 103:1649–1656PubMedGoogle Scholar
  82. 82.
    Lazarowski ER, Mason SJ, Clarke L, Harden TK, Boucher RC (1992) Adenosine receptors on human airway epithelia and their relationship to chloride secretion. Br J Pharmacol 106:774–782PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Eduardo R. Lazarowski
    • 1
  • Juliana I. Sesma
    • 1
  • Lucia Seminario
    • 1
  • Charles R. EstherJr.
    • 2
  • Silvia M. Kreda
    • 1
  1. 1.Cystic Fibrosis Pulmonary Research and Treatment CenterUniversity of North CarolinaChapel HillUSA
  2. 2.Pediatric PulmonologyUniversity of North CarolinaChapel HillUSA

Personalised recommendations