Skip to main content

Advertisement

SpringerLink
Log in

PI3-Kinase-dependent electrogenic intestinal transport of glucose and amino acids

  • Gastrointestinal Function
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Intestinal glucose and amino acid transport is stimulated by the serum- and glucocorticoid-inducible kinase isoforms SGK1, SGK2, and SGK3 and protein kinase B which are, in turn, stimulated following activation of the phosphoinositol-3 kinase (PI3 kinase). The present study has been performed to explore whether pharmacological inhibition of the PI3 kinase affects electrogenic jejunal transport of glucose and amino acids. In Ussing chamber experiments, glucose (20 mM), phenylalanine (20 mM), glutamine (20 mM), cysteine (20 mM), and proline (20 mM) generated lumen negative currents (I glc, I phe, I gln, I cys, and I pro), respectively, which gradually declined following application of the PI3 kinase inhibitor Wortmannin (1 μM). Within 40 min, Wortmannin treatment significantly decreased I glc by 39 ± 10% (n = 5), I phe by 70 ± 7% (n = 4), I gln by 69 ± 8% (n = 4), I cys by 67 ± 8% (n = 6), and I prol by 79 ± 12% (n = 3). A similar decline of I glc was observed following application of the PI3 kinase inhibitor LY294002 (50 μM). Exposure to the inhibitors did not significantly alter transepithelial potential difference and resistance in the absence of substrates for electrogenic transport. The observations suggest that the electrogenic transport of glucose and several amino acids requires the continued activity of PI3 kinase.

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

Similar content being viewed by others

References

  1. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Blazer-Yost BL, Liu X, Helman SI (1998) Hormonal regulation of ENaCs: insulin and aldosterone. Am J Physiol 274:C1373–C1379

    PubMed  CAS  Google Scholar 

  4. Blazer-Yost BL, Paunescu TG, Helman SI, Lee KD, Vlahos CJ (1999) Phosphoinositide 3-kinase is required for aldosterone-regulated sodium reabsorption. Am J Physiol 277:C531–C536

    PubMed  CAS  Google Scholar 

  5. Boehmer C, Henke G, Schniepp R, Palmada M, Rothstein JD, Broer S, Lang F (2003) Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. J Neurochem 86:1181–1188

    Article  PubMed  CAS  Google Scholar 

  6. Boehmer C, Okur F, Setiawan I, Broer S, Lang F (2003) Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB. Biochem Biophys Res Commun 306:156–162

    Article  PubMed  CAS  Google Scholar 

  7. Boehmer C, Philippin M, Rajamanickam J, Mack A, Broer S, Palmada M, Lang F (2005) Glutamate transporter EAAT4 regulation by the ubiquitin ligase Nedd4-2 and serum and glucocorticoid inducible kinases SGK. Biochem Biophys Res Comm (in press)

  8. Boehmer C, Rajamanickam J, Schniepp R, Kohler K, Wulff P, Kuhl D, Palmada M, Lang F (2005) Regulation of the excitatory amino acid transporter EAAT5 by the serum and glucocorticoid dependent kinases SGK1 and SGK3. Biochem Biophys Res Commun 329:738–742

    Article  PubMed  CAS  Google Scholar 

  9. Boehmer C, Palmada M, Rajamanickam J, Schniepp R, Amara S, Lang F (2006) Posttranslational regulation of EAAT2 function by coexpressed ubiquitin ligase Nedd4-2 is impacted by SGK kinases. J Neurochem 97(4):911–921

    Article  PubMed  CAS  Google Scholar 

  10. Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, Pearce D (1999) Epithelial sodium channel regulated by aldosterone-induced protein SGK. Proc Natl Acad Sci USA 96:2514–2519

    Article  PubMed  CAS  Google Scholar 

  11. Coffer PJ, Jin J, Woodgett JR (1998) Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 335(Pt 1):1–13

    PubMed  CAS  Google Scholar 

  12. Coffer PJ, Woodgett JR (1991) Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem 201:475–481

    Article  PubMed  CAS  Google Scholar 

  13. Dieter M, Palmada M, Rajamanickam J, Aydin A, Busjahn A, Boehmer C, Luft FC, Lang F (2004) Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB. Obes Res 12:862–870

    Article  PubMed  CAS  Google Scholar 

  14. Divecha N, Banfic H, Irvine RF (1991) 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 10:3207–3214

    PubMed  CAS  Google Scholar 

  15. Embark HM, Bohmer C, Vallon V, Luft F, Lang F (2003) Regulation of KCNE1-dependent K(+) current by the serum and glucocorticoid-inducible kinase (SGK) isoforms. Pflügers Arch 445:601–606

    PubMed  CAS  Google Scholar 

  16. Embark HM, Bohmer C, Palmada M, Rajamanickam J, Wyatt AW, Wallisch S, Capasso G, Waldegger P, Seyberth HW, Waldegger S, Lang F (2004) Regulation of CLC-Ka/barttin by the ubiquitin ligase Nedd4-2 and the serum- and glucocorticoid-dependent kinases. Kidney Int 66:1918–1925

    Article  PubMed  CAS  Google Scholar 

  17. Embark HM, Setiawan I, Poppendieck S, van de Graaf SF, Boehmer C, Palmada M, Wieder T, Gerstberger R, Cohen P, Yun CC, Bindels RJ, Lang F (2004) Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cell Physiol Biochem 14:203–212

    Article  PubMed  CAS  Google Scholar 

  18. Firestone GL, Giampaolo JR, O’Keeffe BA (2003) Stimulus-dependent regulation of the serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 13:1–12

    Article  PubMed  CAS  Google Scholar 

  19. Gamper N, Fillon S, Huber SM, Feng Y, Kobayashi T, Cohen P, Lang F (2002) IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflügers Arch 443:625–634

    Article  PubMed  CAS  Google Scholar 

  20. Henke G, Maier G, Wallisch S, Boehmer C, Lang F (2004) Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol 199:194–199

    Article  PubMed  CAS  Google Scholar 

  21. Kobayashi T, Cohen P (1999) 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 339:319–328

    Article  PubMed  CAS  Google Scholar 

  22. Kobayashi T, Deak M, Morrice N, Cohen P (1999) Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem J 344:189–197

    Article  PubMed  CAS  Google Scholar 

  23. Kotani K, Yonezawa K, Hara K, Ueda H, Kitamura Y, Sakaue H, Ando A, Chavanieu A, Calas B, Grigorescu F (1994) Involvement of phosphoinositide 3-kinase in insulin- or IGF-1-induced membrane ruffling. EMBO J 13:2313–2321

    PubMed  CAS  Google Scholar 

  24. Lang F, Cohen P (2001) Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Sci STKE 2001:RE17

    Article  PubMed  CAS  Google Scholar 

  25. Lang F, Henke G, Embark HM, Waldegger S, Palmada M, Bohmer C, Vallon V (2003) Regulation of channels by the serum and glucocorticoid-inducible kinase-implications for transport, excitability and cell proliferation. Cell Physiol Biochem 13:41–50

    Article  PubMed  CAS  Google Scholar 

  26. Lang F, Messner G, Rehwald W (1986) Electrophysiology of sodium-coupled transport in proximal renal tubules. Am J Physiol 250:F953–F962

    PubMed  CAS  Google Scholar 

  27. Lang F, Rehwald W (1992) Potassium channels in renal epithelial transport regulation. Physiol Rev 72:1–32

    PubMed  CAS  Google Scholar 

  28. Loffing J, Flores SY, Staub O (2005) Sgk kinases and their role in epithelial transport. Annu Rev Physiol 68:461–490

    Article  CAS  Google Scholar 

  29. Naray-Fejes-Toth A, Canessa C, Cleaveland ES, Aldrich G, Fejes-Toth G (1999) SGK is an aldosterone-induced kinase in the renal collecting duct. Effects on epithelial Na+ channels. J Biol Chem 274:16973–16978

    Article  PubMed  CAS  Google Scholar 

  30. Palmada M, Embark HM, Yun C, Bohmer C, Lang F (2003) Molecular requirements for the regulation of the renal outer medullary K(+) channel ROMK1 by the serum- and glucocorticoid-inducible kinase SGK1. Biochem Biophys Res Commun 311:629–634

    Article  PubMed  CAS  Google Scholar 

  31. Palmada M, Poppendieck S, Embark HM, van de Graaf SF, Boehmer C, Bindels RJ, Lang F (2005) Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1. Cell Physiol Biochem 15:175–182

    Article  PubMed  CAS  Google Scholar 

  32. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA (1999) Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J 18:3024–3033

    Article  PubMed  CAS  Google Scholar 

  33. Rexhepaj R, Artunc F, Grahammer F, Nasir O, Sandu C, Friedrich B, Kuhl D, Lang F (2006) SGK1 is not required for regulation of colonic ENaC activity. Eur J Physiol Pflügers Arch (in press)

  34. Schniepp R, Kohler K, Ladewig T, Guenther E, Henke G, Palmada M, Boehmer C, Rothstein JD, Broer S, Lang F (2004) Retinal colocalization and in vitro interaction of the glutamate transporter EAAT3 and the serum- and glucocorticoid-inducible kinase SGK1 [correction]. Investig Ophthalmol Vis Sci 45:1442–1449

    Article  Google Scholar 

  35. Schultz SG (1981) Homocellular regulatory mechanisms in sodium-transporting epithelia: avoidance of extinction by “flush-through”. Am J Physiol 241:F579–F590

    PubMed  CAS  Google Scholar 

  36. Setiawan I, Henke G, Feng Y, Bohmer C, Vasilets LA, Schwarz W, Lang F (2002) Stimulation of Xenopus oocyte Na(+),K(+)ATPase by the serum and glucocorticoid-dependent kinase SGK1. Pflügers Arch 444:426–431

    Article  PubMed  CAS  Google Scholar 

  37. Vallon V, Grahammer F, Richter K, Bleich M, Lang F, Barhanin J, Volkl H, Warth R (2001) Role of KCNE1-dependent K+ fluxes in mouse proximal tubule. J Am Soc Nephrol 12:2003–2011

    PubMed  CAS  Google Scholar 

  38. Vallon V, Grahammer F, Volkl H, Sandu CD, Richter K, Rexhepaj R, Gerlach U, Rong Q, Pfeifer K, Lang F (2005) KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl Acad Sci USA 102:17864–17869

    Article  PubMed  CAS  Google Scholar 

  39. Wang J, Barbry P, Maiyar AC, Rozansky DJ, Bhargava A, Leong M, Firestone GL, Pearce D (2001) SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport. Am J Physiol Renal Physiol 280:F303–F313

    PubMed  CAS  Google Scholar 

  40. Wärntges S, Klingel K, Weigert C, Fillon S, Buck M, Schleicher E, Rodemann HP, Knabbe C, Kandolf R, Lang F (2002) Excessive transcription of the human serum and glucocorticoid dependent kinase hSGK1 in lung fibrosis. Cell Physiol Biochem 12:135–142

    Article  Google Scholar 

  41. Wulff P, Vallon V, Huang DY, Volkl H, Yu F, Richter K, Jansen M, Schlunz M, Klingel K, Loffing J, Kauselmann G, Bosl MR, Lang F, Kuhl D (2002) Impaired renal Na(+) retention in the sgk1-knockout mouse. J Clin Invest 110:1263–1268

    Article  PubMed  CAS  Google Scholar 

  42. Yoo D, Kim BY, Campo C, Nance L, King A, Maouyo D, Welling PA (2003) Cell surface expression of the ROMK (Kir 1.1) channel is regulated by the aldosterone-induced kinase, SGK-1, and protein kinase A. J Biol Chem 278:23066–23075

    Article  PubMed  CAS  Google Scholar 

  43. Yun CC, Palmada M, Embark HM, Fedorenko O, Feng Y, Henke G, Setiawan I, Boehmer C, Weinman EJ, Sandrasagra S, Korbmacher C, Cohen P, Pearce D, Lang F (2002) The serum and glucocorticoid-inducible kinase SGK1 and the Na(+)/H(+) exchange regulating factor NHERF2 synergize to stimulate the renal outer medullary K(+) channel ROMK1. J Am Soc Nephrol 13:2823–2830

    Article  PubMed  CAS  Google Scholar 

  44. Zecevic M, Heitzmann D, Camargo SM, Verrey F (2004) SGK1 increases Na,K-ATP cell-surface expression and function in Xenopus laevis oocytes. Pflügers Arch 448:29–35

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Rexhep Rexhepaj, Ferruh Artunc & Florian Lang

  2. Department of Anatomy, University of Tübingen, Tübingen, Germany

    Marco Metzger & Thomas Skutella

Authors
  1. Rexhep Rexhepaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ferruh Artunc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Metzger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Skutella
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Florian Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Florian Lang.

Additional information

R. Rexhepaj and F. Artunc shared first authorship.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rexhepaj, R., Artunc, F., Metzger, M. et al. PI3-Kinase-dependent electrogenic intestinal transport of glucose and amino acids. Pflugers Arch - Eur J Physiol 453, 863–870 (2007). https://doi.org/10.1007/s00424-006-0154-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-006-0154-6

Keywords

Search

Navigation