Skip to main content

Advertisement

SpringerLink
Log in

Regulation of basal gastric acid secretion by the glycogen synthase kinase GSK3

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

According to previous observations, basal gastric acid secretion is downregulated by phosphoinositol-3-(PI3)-kinase, phosphoinositide-dependent kinase (PDK1), and protein kinase B (PKBβ/Akt2) signaling. PKB/Akt phosphorylates glycogen synthase kinase GSK3. The present study explored whether PKB/Akt-dependent GSK3-phosphorylation modifies gastric acid secretion.

Methods

Utilizing 2′,7′-bis-(carboxyethyl)-5(6′)-carboxyfluorescein (BCECF)-fluorescence, basal gastric acid secretion was determined from Na+-independent pH recovery (∆pH/min) following an ammonium pulse, which reflects H+/K+-ATPase activity. Experiments were performed in gastric glands from gene-targeted mice (gsk3 KI) with PKB/serum and glucocorticoid-inducible kinase (SGK)-insensitive GSKα,β, in which the serines within the PKB/SGK phosphorylation site were replaced by alanine (GSK3α21A/21A, GSK3β9A/9A).

Results

The cytosolic pH in isolated gastric glands was similar in gsk3 KI and their wild-type littermates (gsk3 WT). However, ∆pH/min was significantly larger in gsk3 KI than in gsk3 WT mice and ∆pH/min was virtually abolished by the H+/K+-ATPase inhibitor omeprazole (100 μM) in gastric glands from both gsk3 KI and gsk3 WT. Plasma gastrin levels were lower in gsk3 KI than in gsk3 WT. Both, an increase of extracellular K+ concentration to 35 mM [replacing Na+/N-methyl-d-glucamine (NMDG)] and treatment with forskolin (5 μM), significantly increased ∆pH/min to virtually the same value in both genotypes. The protein kinase A (PKA) inhibitor H89 (150 nM) and the H2-receptor antagonist ranitidine (100 μM) decreased ∆pH/min in gsk3 KI but not gsk3 WT and again abrogated the differences between the genotypes. The protein abundance of phosphorylated but not of total PKA was significantly larger in gsk3 KI than in gsk3 WT.

Conclusions

Basal gastric acid secretion is enhanced by the disruption of PKB/SGK-dependent phosphorylation and the inhibition of GSK3. Thus, the inhibition of GSK3 participates in the signaling of PI3-kinase-dependent downregulation of basal gastric acid secretion.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Hofer AM, Machen TE. K-induced alkalinization in all cell types of rabbit gastric glands: a novel K/H exchange mechanism. J Membr Biol. 1992;126:245–56.

    PubMed  CAS  Google Scholar 

  2. Hou W, Schubert ML. Gastric secretion. Curr Opin Gastroenterol. 2006;22:593–8.

    Article  PubMed  Google Scholar 

  3. Lee HC, Breitbart H, Berman M, Forte JG. Potassium-stimulated ATPase activity and hydrogen transport in gastric microsomal vesicles. Biochim Biophys Acta. 1979;553:107–31.

    Article  PubMed  CAS  Google Scholar 

  4. Yao X, Forte JG. Cell biology of acid secretion by the parietal cell. Annu Rev Physiol. 2003;65:103–31.

    Article  PubMed  CAS  Google Scholar 

  5. Dedek K, Waldegger S. Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract. Pflugers Arch. 2001;442:896–902.

    Article  PubMed  CAS  Google Scholar 

  6. Heitzmann D, Grahammer F, von Hahn T, Schmitt-Graff A, Romeo E, Nitschke R, et al. Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. J Physiol. 2004;561:547–57.

    Article  PubMed  CAS  Google Scholar 

  7. Heitzmann D, Koren V, Wagner M, Sterner C, Reichold M, Tegtmeier I, et al. KCNE beta subunits determine pH sensitivity of KCNQ1 potassium channels. Cell Physiol Biochem. 2007;19:21–32.

    Article  PubMed  CAS  Google Scholar 

  8. Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young JB, Geibel JP, et al. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem. 2006;281:23740–7.

    Article  PubMed  CAS  Google Scholar 

  9. Vallon V, Grahammer F, Volkl H, Sandu CD, Richter K, Rexhepaj R, et al. KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl Acad Sci USA. 2005;102:17864–9.

    Article  PubMed  CAS  Google Scholar 

  10. Dong MQ, Lau CP, Gao Z, Tseng GN, Li GR. Characterization of recombinant human cardiac KCNQ1/KCNE1 channels (I (Ks)) stably expressed in HEK 293 cells. J Membr Biol. 2006;210:183–92.

    Article  PubMed  CAS  Google Scholar 

  11. Kurokawa J, Chen L, Kass RS. Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc Natl Acad Sci USA. 2003;100:2122–7.

    Article  PubMed  CAS  Google Scholar 

  12. Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR, et al. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002;295:496–9.

    Article  PubMed  CAS  Google Scholar 

  13. Potet F, Scott JD, Mohammad-Panah R, Escande D, Baro I. AKAP proteins anchor cAMP-dependent protein kinase to KvLQT1/IsK channel complex. Am J Physiol Heart Circ Physiol. 2001;280:H2038–45.

    PubMed  CAS  Google Scholar 

  14. Ammar DA, Zhou R, Forte JG, Yao X. Syntaxin 3 is required for cAMP-induced acid secretion: streptolysin O-permeabilized gastric gland model. Am J Physiol Gastrointest Liver Physiol. 2002;282:G23–33.

    PubMed  CAS  Google Scholar 

  15. Mettler SE, Ghayouri S, Christensen GP, Forte JG. Modulatory role of phosphoinositide 3-kinase in gastric acid secretion. Am J Physiol Gastrointest Liver Physiol. 2007;293:G532–43.

    Article  PubMed  CAS  Google Scholar 

  16. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15:6541–51.

    PubMed  CAS  Google Scholar 

  17. Alessi DR, Cohen P. Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev. 1998;8:55–62.

    Article  PubMed  CAS  Google Scholar 

  18. Divecha N, Banfic H, Irvine RF. The polyphosphoinositide cycle exists in the nuclei of Swiss 3T3 cells under the control of a receptor (for IGF-I) in the plasma membrane, and stimulation of the cycle increases nuclear diacylglycerol and apparently induces translocation of protein kinase C to the nucleus. EMBO J. 1991;10:3207–14.

    PubMed  CAS  Google Scholar 

  19. Gamper N, Fillon S, Huber SM, Feng Y, Kobayashi T, Cohen P, et al. IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Arch. 2002;443:625–34.

    Article  PubMed  CAS  Google Scholar 

  20. Kobayashi T, Cohen P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J. 1999;339:319–28.

    Article  PubMed  CAS  Google Scholar 

  21. Kotani K, Yonezawa K, Hara K, Ueda H, Kitamura Y, Sakaue H, et al. Involvement of phosphoinositide 3-kinase in insulin- or IGF-1-induced membrane ruffling. EMBO J. 1994;13:2313–21.

    PubMed  CAS  Google Scholar 

  22. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J. 1999;18:3024–33.

    Article  PubMed  CAS  Google Scholar 

  23. Rotte A, Bhandaru M, Ackermann TF, Boini KM, Lang F. Role of PDK1 in regulation of gastric acid secretion. Cell Physiol Biochem. 2008;22:725–34.

    Article  PubMed  CAS  Google Scholar 

  24. Rotte A, Bhandaaru M, Kempe DS, Pearce D, Birnbaum MJ, Lang F. Regulation of gastric acid secretion by PKB/Akt2. Cell Physiol Biochem. 2010;25:695–704.

    Google Scholar 

  25. Lang PA, Schniepp R, Kirchhoff P, Socrates T, Sidani SM, Geibel JP. PI3 kinase dependent stimulation of gastric acid secretion by dexamethasone. Cell Physiol Biochem. 2007;20:527–34.

    Article  PubMed  CAS  Google Scholar 

  26. Sandu C, Artunc F, Grahammer F, Rotte A, Boini KM, Friedrich B, et al. Role of the serum and glucocorticoid inducible kinase SGK1 in glucocorticoid stimulation of gastric acid secretion. Pflugers Arch. 2007;455:493–503.

    Article  PubMed  CAS  Google Scholar 

  27. Cross HR, Radda GK, Clarke K. The role of Na+/K+ ATPase activity during low flow ischemia in preventing myocardial injury: a 31P, 23Na and 87Rb NMR spectroscopic study. Magn Reson Med. 1995;34:673–85.

    Article  PubMed  CAS  Google Scholar 

  28. Mora A, Sakamoto K, McManus EJ, Alessi DR. Role of the PDK1-PKB-GSK3 pathway in regulating glycogen synthase and glucose uptake in the heart. FEBS Lett. 2005;579:3632–8.

    Article  PubMed  CAS  Google Scholar 

  29. Shaw M, Cohen P, Alessi DR. Further evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 and not by dephosphorylation of Tyr-216. FEBS Lett. 1997;416:307–11.

    Article  PubMed  CAS  Google Scholar 

  30. Sakoda H, Gotoh Y, Katagiri H, Kurokawa M, Ono H, Onishi Y, et al. Differing roles of Akt and serum- and glucocorticoid-regulated kinase in glucose metabolism, DNA synthesis, and oncogenic activity. J Biol Chem. 2003;278:25802–7.

    Article  PubMed  CAS  Google Scholar 

  31. Wyatt AW, Hussain A, Amann K, Klingel K, Kandolf R, Artunc F, et al. DOCA-induced phosphorylation of glycogen synthase kinase 3beta. Cell Physiol Biochem. 2006;17:137–44.

    Article  PubMed  CAS  Google Scholar 

  32. Cohen P, Frame S. The renaissance of GSK3. Nat Rev Mol Cell Biol. 2001;2:769–76.

    Article  PubMed  CAS  Google Scholar 

  33. Cole AR, Sutherland C. Measuring GSK3 expression and activity in cells. Methods Mol Biol. 2008;468:45–65.

    Article  PubMed  CAS  Google Scholar 

  34. McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, et al. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 2005;24:1571–83.

    Article  PubMed  CAS  Google Scholar 

  35. Boini KM, Bhandaru M, Mack A, Lang F. Steroid hormone release as well as renal water and electrolyte excretion of mice expressing PKB/SGK-resistant GSK3. Pflugers Arch. 2008;456:1207–16.

    Article  PubMed  CAS  Google Scholar 

  36. Boini KM, Amann K, Kempe D, Alessi DR, Lang F. Proteinuria in mice expressing PKB/SGK-resistant GSK3. Am J Physiol Ren Physiol. 2009;296:F153–9.

    Article  CAS  Google Scholar 

  37. Waisbren SJ, Geibel J, Boron WF, Modlin IM. Luminal perfusion of isolated gastric glands. Am J Physiol. 1994;266:C1013–27.

    PubMed  CAS  Google Scholar 

  38. Roos A, Boron WF. Intracellular pH. Physiol Rev. 1981;61:296–434.

    PubMed  CAS  Google Scholar 

  39. Boyarsky G, Ganz MB, Sterzel RB, Boron WF. pH regulation in single glomerular mesangial cells. I. Acid extrusion in absence and presence of HCO3 −. Am J Physiol. 1988;255:C844–56.

    PubMed  CAS  Google Scholar 

  40. Gawenis LR, Greeb JM, Prasad V, Grisham C, Sanford LP, Doetschman T, et al. Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H+ exchanger. J Biol Chem. 2005;280:12781–9.

    Article  PubMed  CAS  Google Scholar 

  41. Grahammer F, Herling AW, Lang HJ, Schmitt-Graff A, Wittekindt OH, Nitschke R, et al. The cardiac K+ channel KCNQ1 is essential for gastric acid secretion. Gastroenterology. 2001;120:1363–71.

    Article  PubMed  CAS  Google Scholar 

  42. Lee MP, Ravenel JD, Hu RJ, Lustig LR, Tomaselli G, Berger RD, et al. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J Clin Invest. 2000;106:1447–55.

    Article  PubMed  CAS  Google Scholar 

  43. Lang F, Bohmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev. 2006;86:1151–78.

    Article  PubMed  CAS  Google Scholar 

  44. Busjahn A, Seebohm G, Maier G, Toliat MR, Nurnberg P, Aydin A, et al. Association of the serum and glucocorticoid regulated kinase (sgk1) gene with QT interval. Cell Physiol Biochem. 2004;14:135–42.

    Article  PubMed  CAS  Google Scholar 

  45. Embark HM, Bohmer C, Vallon V, Luft F, Lang F. Regulation of KCNE1-dependent K(+) current by the serum and glucocorticoid-inducible kinase (SGK) isoforms. Pflugers Arch. 2003;445:601–6.

    PubMed  CAS  Google Scholar 

  46. Seebohm G, Strutz-Seebohm N, Birkin R, Dell G, Bucci C, Spinosa MR, et al. Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ Res. 2007;100:686–92.

    Article  PubMed  CAS  Google Scholar 

  47. Luo JC, Lin HY, Lu CL, Wang LY, Chang FY, Lin HC, et al. Dexamethasone inhibits basic fibroblast growth factor-stimulated gastric epithelial cell proliferation. Biochem Pharmacol. 2008;76:841–9.

    Article  PubMed  CAS  Google Scholar 

  48. Yokota A, Taniguchi M, Takahira Y, Tanaka A, Takeuchi K. Dexamethasone damages the rat stomach but not small intestine during inhibition of COX-1. Dig Dis Sci. 2007;52:1452–61.

    Article  PubMed  CAS  Google Scholar 

  49. Wallace JL, Caliendo G, Santagada V, Cirino G, Fiorucci S. Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology. 2007;132:261–71.

    Article  PubMed  CAS  Google Scholar 

  50. Wang GZ, Huang GP, Yin GL, Zhou G, Guo CJ, Xie CG, et al. Aspirin can elicit the recurrence of gastric ulcer induced with acetic acid in rats. Cell Physiol Biochem. 2007;20:205–12.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the DFG (GRK 1301, SFB 773). The authors gratefully acknowledge the meticulous preparation of the manuscript by Lejla Subasic.

Author information

Authors and Affiliations

  1. Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany

    Anand Rotte, Venkanna Pasham, Melanie Eichenmüller, Wenting Yang, Syed M. Qadri, Madhuri Bhandaru & Florian Lang

Authors
  1. Anand Rotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Venkanna Pasham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melanie Eichenmüller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenting Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Syed M. Qadri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Madhuri Bhandaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Florian Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Florian Lang.

Additional information

A. Rotte and V. Pasham contributed equally and thus share first authorship.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rotte, A., Pasham, V., Eichenmüller, M. et al. Regulation of basal gastric acid secretion by the glycogen synthase kinase GSK3. J Gastroenterol 45, 1022–1032 (2010). https://doi.org/10.1007/s00535-010-0260-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-010-0260-2

Keywords

Search

Navigation