Gastroenterology
Volume 138, Issue 2 , Pages 649-658 , February 2010

Lysophosphatidic Acid Stimulates the Intestinal Brush Border Na+/H+ Exchanger 3 and Fluid Absorption via LPA5 and NHERF2

  • Songbai Lin

      Affiliations

    • Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
    • ,
  • Sunil Yeruva

      Affiliations

    • Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Peijian He

      Affiliations

    • Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
    • ,
  • Anurag Kumar Singh

      Affiliations

    • Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Huanchun Zhang

      Affiliations

    • Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
    • ,
  • Mingmin Chen

      Affiliations

    • Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • Georg Lamprecht

      Affiliations

    • Department of Medicine, University of Tübingen, Tübingen, Germany
    • ,
  • Hugo R. de Jonge

      Affiliations

    • Department of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
    • ,
  • Ming Tse

      Affiliations

    • Departments of Medicine and Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Mark Donowitz

      Affiliations

    • Departments of Medicine and Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • ,
  • Boris M. Hogema

      Affiliations

    • Department of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
    • ,
  • Jerold Chun

      Affiliations

    • Department of Molecular Biology, Scripps Research Institute, La Jolla, California
    • ,
  • Ursula Seidler

      Affiliations

    • Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
    • ,
  • C. Chris Yun

      Affiliations

    • Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
    • Department of Physiology, Emory University School of Medicine, Atlanta, Georgia
    • Corresponding Author InformationReprint requests Address requests for reprints to: C. Chris Yun, PhD, Division of Digestive Diseases, Emory University School of Medicine, Whitehead Building, Room 201, 615 Michael Street, Atlanta, Georgia 30322

Received 9 July 2009 ,Accepted 23 September 2009.

References 

  1. Field M. Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest. 2003;111:931–943
  2. Zachos NC, Tse M, Donowitz M. Molecular physiology of intestinal Na+/H+ exchanger. Ann Rev Physiol. 2005;67:411–443
  3. Schultheis PJ, Clarke LL, Meneton P, et al. Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet. 1998;19:282–285
  4. Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer. 2003;3:582–591
  5. Noguchi K, Herr D, Mutoh T, et al. Lysophosphatidic acid (LPA) and its receptors. Curr Opin Pharmacol. 2009;9:15–23
  6. Choi S, Lee M, Shiu AL, et al. Identification of a protein hydrolysate responsive G protein-coupled receptor in enterocytes. Am J Physiol. 2007;292:G98–G112
  7. Lee C-W, Rivera R, Gardell S, et al. GPR92 as a New G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J Biol Chem. 2006;281:23589–23597
  8. Yun CC, Sun H, Wang D, et al. LPA2 receptor mediates mitogenic signals in human colon cancer cells. Am J Physiol. 2005;289:C2–C11
  9. Li C, Dandridge KS, Di A, et al. Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions. J Exp Med. 2005;202:975–986
  10. Singh AK, Riederer B, Krabbenhoft A, et al. Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice. J Clin Invest. 2009;119:540–550
  11. Lee-Kwon W, Kawano K, Choi JW, et al. Lysophosphatidic acid stimulates brush border Na+/H+ exchanger 3 (NHE3) activity by increasing its exocytosis by an NHE3 kinase A regulatory protein-dependent mechanism. J Biol Chem. 2003;278:16494–16501
  12. Choi JW, Lee-Kwon W, Jeon ES, et al. Lysophosphatidic acid induces exocytic trafficking of Na+/H+ exchanger 3 by E3KARP-dependent activation of phospholipase C. Biochim Biophys Acta. 2004;1683:59–68
  13. Lin S, Wang D, Iyer S, et al. The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer. Gastroenterology. 2009;136:1711–1720
  14. Yun CC, Chen Y, Lang F. Glucocorticoid activation of Na+/H+ exchanger isoform 3 revisited (The roles of SGK1 and NHERF2). J Biol Chem. 2002;277:7676–7683
  15. Clayburgh DR, Barrett TA, Tang Y, et al. Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J Clin Invest. 2005;115:2702–2715
  16. Cinar A, Chen MM, Riederer B, et al. Nhe3 inhibition by cAMP and Ca2+ is abolished in PDZ-domain protein PDZK1-deficient murin enterocytes. J Physiol. 2007;581:1235–1246
  17. Yun CC, Oh S, Zizak M, et al. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc Natl Acad Sci U S A. 1997;94:3010–3015
  18. Gisler SM, Pribanic S, Bacic D, et al. PDZK1: I. A major scaffolder in brush borders of proximal tubular cells1. Kidney Int. 2003;64:1733–1745
  19. Oh DY, Yoon JM, Moon MJ, et al. Identification of farnesyl pyrophosphate and N-arachidonylglycine as endogenous ligands for GPR92. J Biol Chem. 2008;283:21054–21064
  20. Miyazawa D, Ikemoto A, Fujii Y, et al. Dietary alpha-linolenic acid suppresses the formation of lysophosphatidic acid, a lipid mediator, in rat platelets compared with linoleic acid. Life Sci. 2003;73:2083–2090
  21. Nakane S, Tokumura A, Waku K, et al. Hen egg yolk and white contain high amounts of lysophosphatidic acids, growth factor-like lipids: distinct molecular species compositions. Lipids. 2001;36:413–419
  22. Tokumura A, Kanaya Y, Kitahara M, et al. Increased formation of lysophosphatidic acids by lysophospholipase D in serum of hypercholesterolemic rabbits. J Lipid Res. 2002;43:307–315
  23. Aoki J, Taira A, Takanezawa Y, et al. Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem. 2002;277:48737–48744
  24. Maher MM, Gontarek JD, Jimenez RE, et al. Role of brush border Na+/H+ exchange in canine ileal absorption. Dig Dis Sci. 1996;41:651–659
  25. Mills GB, May C, McGill M, et al. A putative new growth factor in ascitic fluid from ovarian cancer patients: identification, characterization, and mechanism of action. Cancer Res. 1988;48:1066–1071
  26. Lamprecht G, Seidler U. The emerging role of PDZ adapter proteins for regulation of intestinal ion transport. Am J Physiol. 2006;291:G766–G777
  27. Shenolikar S, Voltz JW, Minkoff CM, et al. Targeted disruption of the mouse NHERF-1 gene promotes internalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A. 2002;8:8
  28. Broere N, Chen M, Cinar A, et al. Defective jejunal and colonic salt absorption and altered Na+/H+ exchanger 3 (NHE3) activity in NHE regulatory factor 1 (NHERF1) adaptor protein-deficient mice. Pflugers Arch. 2009;457:1079–1091
  29. Oh YS, Jo NW, Choi JW, et al. NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation. Mol Cell Biol. 2004;24:5069–5079
  30. Hiroyama M, Takenawa T. Isolation of a cDNA encoding human lysophosphatidic acid phosphatase that is involved in the regulation of mitochondrial lipid biosynthesis. J Biol Chem. 1999;274:29172–29180
  31. Deng W, Shuyu E, Tsukahara R, et al. The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury. Gastroenterology. 2007;132:1834–1851

 Conflicts of interest The authors disclose no conflicts.

 Funding This work was funded by National Institutes of Health grants DK061416 (CCY), MH51699 and HD50685 (JC) and by DFG SFB621-C9 (US). SL was supported by the Crohn's and Colitis Foundation of America. PH was supported by the American Heart Association. AS and MC were supported by postdoctoral stipends of the Hannover biomedical Research School that were funded by the DAAD and Abbot GmbH via the “matching fund” program. We thank the Emory Digestive Disease Research Development Center (supported by DK064399) for the use of light microscope and the Zeiss 510 confocal microscope and the Volkswagen Stiftung for funding of the Leica LSM.

PII: S0016-5085(09)01750-8

doi: 10.1053/j.gastro.2009.09.055

Gastroenterology
Volume 138, Issue 2 , Pages 649-658 , February 2010

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