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Distal colonic Na+ absorption inhibited by luminal P2Y2 receptors

  • Gastrointestinal Function
  • Published:
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Abstract

Luminal P2 receptors are ubiquitously expressed in transporting epithelia. In steroid-sensitive epithelia (e.g., lung, distal nephron) epithelial Na+ channel (ENaC)-mediated Na+ absorption is inhibited via luminal P2 receptors. In distal mouse colon, we have identified that both, a luminal P2Y2 and a luminal P2Y4 receptor, stimulate K+ secretion. In this study, we investigate the effect of luminal adenosine triphosphate/uridine triphosphate (ATP/UTP) on electrogenic Na+ absorption in distal colonic mucosa of mice treated on a low Na+ diet for more than 2 weeks. Transepithelial electrical parameters were recorded in an Ussing chamber. Baseline parameters: transepithelial voltage (V te): −13.7 ± 1.9 mV (lumen negative), transepithelial resistance (R te): 24.1 ± 1.8 Ω cm2, equivalent short circuit current (I sc): −563.9 ± 63.8 μA/cm2 (n = 21). Amiloride completely inhibited I sc to −0.5 ± 8.5 μA/cm2. Luminal ATP induced a slowly on-setting and persistent inhibition of the amiloride-sensitive I sc by 160.7 ± 29.7 μA/cm2 (n = 12, NMRI mice). Luminal ATP and UTP were almost equipotent with IC50 values of 10 μM and 3 μM respectively. In P2Y2 knock-out (KO) mice, the effect of luminal UTP on amiloride-sensitve Na+ absorption was absent. In contrast, in P2Y4 KO mice the inhibitory effect of luminal UTP on Na+ absorption remained present. Semiquantitative polymerase chain reaction did not indicate regulation of the P2Y receptors under low Na+ diet, but it revealed a pronounced axial expression of both receptors with highest abundance in surface epithelia. Thus, luminal P2Y2 and P2Y4 receptors and ENaC channels co-localize in surface epithelium. Intriguingly, only the stimulation of the P2Y2 receptor mediates inhibition of electrogenic Na+ absorption.

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References

  1. Binder HJ, Sandle GI (1994) Electrolyte transport in the mammalian colon. In: Johnson LR (ed) Physiology of the gastrointestinal tract. Raven, New York, pp 2133–2171

    Google Scholar 

  2. Boucher RC (2003) Regulation of airway surface liquid volume by human airway epithelia. Pflügers Arch 445:495–498

    PubMed  CAS  Google Scholar 

  3. Crane JK, Olson RA, Jones HM, Duffey ME (2002) Release of ATP during host cell killing by enteropathogenic E. coli and its role as a secretory mediator. Am J Physiol Gastrointest Liver Physiol 283:G74–G86

    PubMed  CAS  Google Scholar 

  4. Cressman VL, Lazarowski ER, Homolya L, Boucher RC, Koller BH, Grubb BR (1999) Effect of loss of P2Y2 receptor gene expression on nucleotide regulation of murine epithelial Cl− transport. J Biol Chem 274:26461–26468

    Article  PubMed  CAS  Google Scholar 

  5. Cuffe JE, Bielfeld-Ackermann A, Thomas J, Leipziger J, Korbmacher C (2000) ATP stimulates Cl− secretion and reduces amiloride-sensitive Na+ absorption in M-1 mouse cortical collecting duct cells. J Physiol 524:77–90

    Article  PubMed  CAS  Google Scholar 

  6. Devor DC, Pilewski JM (1999) UTP inhibits Na+ absorption in wild-type and DeltaF508 CFTR-expressing human bronchial epithelia. Am J Physiol 276:C827–C837

    PubMed  CAS  Google Scholar 

  7. Dubyak GR (2003) Knock-out mice reveal tissue-specific roles of P2Y receptor subtypes in different epithelia. Mol Pharmacol 63:773–776

    Article  PubMed  CAS  Google Scholar 

  8. Garty H, Palmer LG (1997) Epithelial sodium channels: function, structure, and regulation. Physiol Rev 77:359–451

    PubMed  CAS  Google Scholar 

  9. Greger R, Bleich M, Leipziger J, Ecke D, Mall M, Kunzelmann K (1997) Regulation of ion transport in colonic crypts. Nips 12:62–66

    CAS  Google Scholar 

  10. Hilgemann DW, Feng S, Nasuhoglu C (2001) The complex and intriguing lives of PIP2 with ion channels and transporters. Sci STKE. RE19

  11. Homolya L, Watt WC, Lazarowski ER, Koller BH, Boucher RC (1999) Nucleotide-regulated calcium signaling in lung fibroblasts and epithelial cells from normal and P2Y(2) receptor (−/−) mice. J Biol Chem 274:26454–26460

    Article  PubMed  CAS  Google Scholar 

  12. Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, Schmidt A, Boucher R, Rossier BC (1996) Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice. Nat Genet 12:325–328

    Article  PubMed  CAS  Google Scholar 

  13. Inglis SK, Collett A, McAlroy HL, Wilson SM, Olver RE (1999) Effect of luminal nucleotides on Cl− secretion and Na+ absorption in distal bronchi. Pflügers Arch 438:621–627

    Article  PubMed  CAS  Google Scholar 

  14. Janssens R, Paindavoine P, Parmentier M, Boeynaems JM (1999) Human P2Y2 receptor polymorphism: identification and pharmacological characterization of two allelic variants. Br J Pharmacol 127:709–716

    Article  PubMed  CAS  Google Scholar 

  15. Kerstan D, Gordjani N, Nitschke R, Greger R, Leipziger J (1998) Luminal ATP induces K+ secretion via a P2Y2 receptor in rat distal colonic mucosa. Pflügers Arch 436:712–716

    Article  PubMed  CAS  Google Scholar 

  16. 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

    PubMed  CAS  Google Scholar 

  17. Kunzelmann K, Konig J, Sun J, Markovich D, King NJ, Karupiah G, Young JA, Cook DI (2004) Acute effects of parainfluenza virus on epithelial electrolyte transport. J Biol Chem 279:48760–48766

    Article  PubMed  CAS  Google Scholar 

  18. Kunzelmann K, Mall M (2002) Electrolyte transport in the Mammalian colon: mechanisms and implications for disease. Physiol Rev 82:245–289

    PubMed  CAS  Google Scholar 

  19. Kunzelmann K, McMorran B (2004) First encounter: how pathogens compromise epithelial transport. Physiology 19:240–244

    Article  PubMed  CAS  Google Scholar 

  20. Kunzelmann K, Schreiber R, Cook D (2002) Mechanisms for the inhibition of amiloride-sensitive Na+ absorption by extracellular nucleotides in mouse trachea. Pflügers Arch 444:220–226

    Article  PubMed  CAS  Google Scholar 

  21. Lazarowski ER, Boucher RC, Harden TK (2003) Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 64:785–795

    Article  PubMed  CAS  Google Scholar 

  22. 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

    Article  PubMed  CAS  Google Scholar 

  23. Lehrmann H, Thomas J, Kim SJ, Jacobi C, Leipziger J (2002) Luminal P2Y2 receptor-mediated inhibition of Na+ absorption in isolated perfused mouse CCD. J Am Soc Nephrol 13:10–18

    PubMed  CAS  Google Scholar 

  24. Leipziger J (2003) Control of epithelial transport via luminal P2 receptors. Am J Physiol Renal Physiol 284:F419–F432

    PubMed  CAS  Google Scholar 

  25. Lohrmann E, Burhoff I, Nitschke RB, Lang HJ, Mania D, Englert HC, Hropot M, Warth R, Rohm W, Bleich M, Greger R (1995) A new class of inhibitors of cAMP-mediated Cl− secretion in rabbit colon, acting by the reduction of cAMP-activated K+ conductance. Pflügers Arch 429:517–530

    Article  PubMed  CAS  Google Scholar 

  26. Ma HP, Eaton DC (2005) Acute regulation of epithelial sodium channel by anionic phospholipids. J Am Soc Nephrol 16:3182–3187

    Article  PubMed  CAS  Google Scholar 

  27. Mall M, Wissner A, Gonska T, Calenborn D, Kuehr J, Brandis M, Kunzelmann K (2000) Inhibition of amiloride-sensitive epithelial Na+ absorption by extracellular nucleotides in human normal and cystic fibrosis airways. Am J Respir Cell Mol Biol 23:755–761

    PubMed  CAS  Google Scholar 

  28. Matos JE, Robaye B, Boeynaems JM, Beauwens R, Leipziger J (2005) K+ secretion activated by luminal P2Y2 and P2Y4 receptors in mouse colon. J Physiol 564:269–279

    Article  PubMed  CAS  Google Scholar 

  29. McCoy DE, Taylor AL, Kudlow BA, Karlson K, Slattery MJ, Schwiebert LM, Schwiebert EM, Stanton BA (1999) Nucleotides regulate NaCl transport in mIMCD-K2 cells via P2X and P2Y purinergic receptors. Am J Physiol 277:F552–F559

    PubMed  CAS  Google Scholar 

  30. McNamara N, Khong A, McKemy D, Caterina M, Boyer J, Julius D, Basbaum C (2001) ATP transduces signals from ASGM1, a glycolipid that functions as a bacterial receptor. Proc Natl Acad Sci USA 98:9086–9091

    Article  PubMed  CAS  Google Scholar 

  31. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492

    PubMed  CAS  Google Scholar 

  32. Robaye B, Ghanem E, Wilkin F, Fokan D, Van Driessche W, Schurmans S, Boeynaems J-M, Beauwens R (2003) Loss of nucleotide regulation of epithelial chloride transport in the jejunum of P2Y4-null mice. Mol Pharmacol 64:777–783

    Article  Google Scholar 

  33. Rouch AJ, Chen L, Kudo LH, Bell PD, Fowler BC, Corbitt BD, Schafer JA (1993) Intracellular Ca2+and PKC activation do not inhibit Na+ and water transport in rat CCD. Am J Physiol 265:F569–F577

    PubMed  CAS  Google Scholar 

  34. Sausbier M, Matos JE, Sausbier U, Beranek G, Arntz C, Neuhuber W, Ruth P, Leipziger J (2006) Distal colonic K+ secretion occurs via BK channels. J Am Soc Nephrol 17:1275–1282

    Article  PubMed  CAS  Google Scholar 

  35. Siemer C, Gögelein H (1990) Nonselective cation-channels in the basolateral membrane of crypt cells from rat distal colon. Pflügers Arch 415:R46

    Google Scholar 

  36. Thomas J, Deetjen P, Ko WH, Jacobi C, Leipziger J (2001) P2Y2 receptor-mediated inhibition of amiloride-sensitive short circuit current in M-1 mouse cortical collecting duct cells. J Membr Biol 183:115–124

    Article  PubMed  CAS  Google Scholar 

  37. Tran VN, Clair C, Bruzzone R, Mesnil M, Sansonetti P, Combettes L (2003) Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells. Nat Cell Biol 5:720–726

    Article  Google Scholar 

  38. Wald H, Goldstein O, Asher C, Yagil Y, Garty H (1996) Aldosterone induction and epithelial distribution of CHIF. Am J Physiol 271:F322–F329

    PubMed  CAS  Google Scholar 

  39. Will PC, Cortright RN, DeLisle RC, Douglas JG, Hopfer U (1985) Regulation of amiloride-sensitive electrogenic sodium transport in the rat colon by steroid hormones. Am J Physiol 248:G124–G132

    PubMed  CAS  Google Scholar 

  40. Yamamoto T, Suzuki Y (2002) Role of luminal ATP in regulating electrogenic Na+ absorption in guinea pig distal colon. Am J Physiol Gastrointest Liver Physiol 283:G300–G308

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the expert technical assistance of Edith Bjørn Møller and Ann-Charlotte Andersen.

This study was supported by the Danish Medical Research Council and the Portuguese Foundation for Science and Technology.

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Authors and Affiliations

  1. Institute of Physiology and Biophysics, The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark

    J. E. Matos, M. V. Sorensen, C. S. Geyti & J. Leipziger

  2. Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine, Université Libre de Bruxelles, Gosselies, Belgium

    B. Robaye & J. M. Boeynaems

  3. Laboratory of Medical Chemistry, Erasme Hospital, Université Libre de Bruxelles, Gosselies, Belgium

    J. M. Boeynaems

  4. Ole Worms Allé 160, 8000, Aarhus, Denmark

    J. Leipziger

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  1. J. E. Matos
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  3. C. S. Geyti
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  4. B. Robaye
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Correspondence to J. Leipziger.

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Matos, J.E., Sorensen, M.V., Geyti, C.S. et al. Distal colonic Na+ absorption inhibited by luminal P2Y2 receptors. Pflugers Arch - Eur J Physiol 454, 977–987 (2007). https://doi.org/10.1007/s00424-007-0248-9

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  • DOI: https://doi.org/10.1007/s00424-007-0248-9

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