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.
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Notes
- 1.
We use the term “constitutive” to refer to a release process that occurs in non-stimulated cells.
References
Burnstock G (2006) Purinergic signaling-an overview. Novartis Found Symp 276:26–48
von Kügelgen I (2006) Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol Ther 110:415–432
Surprenant A, North RA (2009) Signaling at purinergic P2X receptors. Annu Rev Physiol 71:333–359
Fredholm BB (2010) Adenosine receptors as drug targets. Exp Cell Res 316:1284–1288
Ciruela F, Albergaria C, Soriano A, CuffĂ L, Carbonell L, Sánchez S, GandĂa J, Fernández-Dueñas V (2010) Adenosine receptors interacting proteins (ARIPs): behind the biology of adenosine signaling. Biochim Biophys Acta 1798:9–20
Trincavelli ML, Daniele S, Martini C (2010) Adenosine receptors: what we know and what we are learning. Curr Top Med Chem 10:860–877
Lazarowski ER, Boucher RC (2009) Purinergic receptors in airway epithelia. Curr Opin Pharmacol 9:262–267
Davis CW, Dickey BF (2008) Regulated airway goblet cell mucin secretion. Annu Rev Physiol 70:487–512
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–C1497
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 272:4978–4984
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–C837
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 277:11965–11969
Ma HP, Saxena S, Warnock DG (2002) Anionic phospholipids regulate native and expressed epithelial sodium channel (ENaC). J Biol Chem 277:7641–7644
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 19:142–143
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 322:590–594
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 455:1210–1215
Schroeder BC, Cheng T, Jan YN, Jan LY (2008) Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 134:1019–1029
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 94:2599–2603
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 33:601–609
Barth K, Kasper M (2009) Membrane compartments and purinergic signaling: occurrence and function of P2X receptors in lung. FEBS J 276:341–353
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 104:875–884
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 571:503–517
North RA, Surprenant A (2000) Pharmacology of cloned P2X receptors. Annu Rev Pharmacol Toxicol 40:563–580
Rettinger J, Schmalzing G (2003) Activation and desensitization of the recombinant P2X1 receptor at nanomolar ATP concentrations. J Gen Physiol 121:451–461
Rettinger J, Schmalzing G (2004) Desensitization masks nanomolar potency of ATP for the P2X1 receptor. J Biol Chem 279:6426–6433
Guo C, Masin M, Qureshi OS, Murrell-Lagnado RD (2007) Evidence for functional P2X4/P2X7 heteromeric receptors. Mol Pharmacol 72:1447–1456
North RA (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067
Boucher RC (2002) An overview of the pathogenesis of cystic fibrosis lung disease. Adv Drug Deliv Rev 54:1359–1371
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–L855
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 55:378–385
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 177:7173–7183
Sun Y, Wu F, Sun F, Huang P (2008) Adenosine promotes IL-6 release in airway epithelia. J Immunol 180:4173–4181
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 279:36855–36864
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 281:22992–23002
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 6:969–982
Button B, Boucher RC (2008) Role of mechanical stress in regulating airway surface hydration and mucus clearance rates. Respir Physiol Neurobiol 163:189–201
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 280:35751–35759
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 127:591–604
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 580:577–592
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 278:33436–33444
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 47:9269–9278
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 275:10767–10771
Lazarowski ER, Shea DA, Boucher RC, Harden TK (2003) Release of cellular UDP-glucose as a potential extracellular signaling molecule. Mol Pharmacol 63:1190–1197
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 584:245–259
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 284:12572–12583
Perez M, Hirschberg CB (1986) Topography of glycosylation reactions in the rough endoplasmic reticulum membrane. J Biol Chem 261:6822–6830
Parodi AJ (2000) Protein glucosylation and its role in protein folding. Annu Rev Biochem 69:69–93
Berninsone PM, Hirschberg CB (2000) Nucleotide sugar transporters of the Golgi apparatus. Curr Opin Struct Biol 10:542–547
Ishida N, Kawakita M (2004) Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflügers Arch 447:768–775
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 279:26469–26474
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 85:106–116
Guillén E, Hirschberg CB (1995) Transport of adenosine triphosphate into endoplasmic reticulum proteoliposomes. Biochemistry 34:5472–5476
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 67:49–69
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 271:17132–17138
Scrivens M, Dickenson JM (2005) Functional expression of the P2Y14 receptor in murine T-lymphocytes. Br J Pharmacol 146:435–444
Scrivens M, Dickenson JM (2006) Functional expression of the P2Y14 receptor in human neutrophils. Eur J Pharmacol 543:166–173
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 330:162–168
Boudreault F, Grygorczyk R (2004) Cell swelling-induced ATP release is tightly dependent on intracellular calcium elevations. J Physiol 561:499–513
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 584:419–435
Tatur S, Kreda S, Lazarowski E, Grygorczyk R (2008) Calcium-dependent release of adenosine and uridine nucleotides from A549 cells. Purinergic Signal 4:139–146
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 284:20638–20648
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 278:23331–23342
Kreda SM, Seminario-Vidal L, Heusden C, Lazarowski E (2008) Thrombin-promoted release of UDP-glucose from human astrocytoma cells. Br J Pharmacol 153:1528–1537
Blum AE, Joseph SM, Przybylski RJ, Dubyak GR (2008) Rho-family GTPases modulate Ca2+-dependent ATP release from astrocytes. Am J Physiol 295:C231–C241
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 558:479–488
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 168:3577–3585
Hains MD, Siderovski DP, Harden TK (2004) Application of RGS box proteins to evaluate G-protein selectivity in receptor-promoted signaling. Methods Enzymol 389:71–88
Scemes E, Suadicani SO, Dahl G, Spray DC (2007) Connexin and pannexin mediated cell-cell communication. Neuron Glia Biol 3:199–208
Boassa D, Qiu F, Dahl G, Sosinsky G (2008) Trafficking dynamics of glycosylated pannexin 1 proteins. Cell Commun Adhes 15:119–132
Dahl G, Locovei S (2006) Pannexin: to gap or not to gap, is that a question? IUBMB Life 58:409–419
Goodenough DA, Paul DL (2003) Beyond the gap: functions of unpaired connexon channels. Nat Rev Mol Cell Biol 4:285–294
Müller DJ, Hand GM, Engel A, Sosinsky GE (2002) Conformational changes in surface structures of isolated connexin 26 gap junctions. EMBO J 21:3598–3607
Shestopalov VI, Panchin Y (2008) Pannexins and gap junction protein diversity. Cell Mol Life Sci 65:376–394
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 100:16030–16035
Stout CE, Costantin JL, Naus CC, Charles AC (2002) Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277:10482–10488
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 25:34–44
Bruzzone R, Barbe MT, Jakob NJ, Monyer H (2005) Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytes. J Neurochem 92:1033–1043
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–C241
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 41:525–534
Locovei S, Wang J, Dahl G (2006) Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett 580:239–244
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 103:1649–1656
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 106:774–782
Acknowledgments
We would like to thank Lisa Brown for editorial assistance of the manuscript. This work was supported by the National Institute of Health (NIH), National Heart, Lung, and Blood Institute (P01-HL034322) and the Cystic Fibrosis Foundation (CFF-SEMINA08FO).
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Lazarowski, E.R., Sesma, J.I., Seminario, L., Esther, C.R., Kreda, S.M. (2011). Nucleotide Release by Airway Epithelia. In: Picher, M., Boucher, R. (eds) Purinergic Regulation of Respiratory Diseases. Subcellular Biochemistry, vol 55. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1217-1_1
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