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Molecular Pharmacology

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Research ArticleArticle

Protein RS1 (RSC1A1) Downregulates the Exocytotic Pathway of Glucose Transporter SGLT1 at Low Intracellular Glucose via Inhibition of Ornithine Decarboxylase

Chakravarthi Chintalapati, Thorsten Keller, Thomas D. Mueller, Valentin Gorboulev, Nadine Schäfer, Ilona Zilkowski, Maike Veyhl-Wichmann, Dietmar Geiger, Jürgen Groll and Hermann Koepsell
Molecular Pharmacology November 2016, 90 (5) 508-521; DOI: https://doi.org/10.1124/mol.116.104521
Chakravarthi Chintalapati
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Thorsten Keller
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Thomas D. Mueller
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Valentin Gorboulev
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Nadine Schäfer
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Ilona Zilkowski
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Maike Veyhl-Wichmann
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Dietmar Geiger
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Jürgen Groll
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Hermann Koepsell
Institute of Anatomy and Cell Biology (C.C., V.G., M.V.-W., H.K.), and Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute (T.K., T.D.M., N.S., D.G., H.K.), University of Würzburg, Würzburg, Germany; and Department of Functional Materials in Medicine and Dentistry, University Hospital Würzburg, Würzburg, Germany (I.Z., J.G.)
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Abstract

Na+-d-glucose cotransporter 1 (SGLT1) is rate-limiting for glucose absorption in the small intestine. Shortly after intake of glucose-rich food, SGLT1 abundance in the luminal membrane of the small intestine is increased. This upregulation occurs via glucose-induced acceleration of the release of SGLT1-containing vesicles from the trans-Golgi network (TGN), which is regulated by a domain of protein RS1 (RSC1A1) named RS1-Reg. Dependent on phosphorylation, RS1-Reg blocks release of vesicles containing SGLT1 or concentrative nucleoside transporter 1. The hypothesis has been raised that RS1-Reg binds to different receptor proteins at the TGN, which trigger release of vesicles with different transporters. To identify the presumed receptor proteins, two-hybrid screening was performed. Interaction with ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme of polyamine synthesis, was observed and verified by immunoprecipitation. Binding of RS1-Reg mutants to ODC1 was characterized using surface plasmon resonance. Inhibition of ODC1 activity by RS1-Reg mutants and the ODC1 inhibitor difluoromethylornithine (DFMO) was measured in the absence and presence of glucose. In addition, short-term effects of DFMO, RS1-Reg mutants, the ODC1 product putrescine, and/or glucose on SGLT1 expressed in oocytes of Xenopus laevis were investigated. High-affinity binding of RS1-Reg to ODC1 was demonstrated, and evidence for a glucose binding site in ODC1 was provided. Binding of RS1-Reg to ODC1 inhibits the enzymatic activity at low intracellular glucose, which is blunted at high intracellular glucose. The data suggest that generation of putrescine by ODC1 at the TGN stimulates release of SGLT1-containing vesicles. This indicates a biomedically important role of ODC1 in regulation of glucose homeostasis.

Footnotes

    • Received March 31, 2016.
    • Accepted August 16, 2016.
  • ↵1 C.C. and T.K. contributed equally to this work.

  • This study was funded by the Deutsche Forschungsgemeinschaft [Grant SFB 487/C1].

  • dx.doi.org/10.1124/mol.116.104521.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 90 (5)
Molecular Pharmacology
Vol. 90, Issue 5
1 Nov 2016
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Research ArticleArticle

Short-Term Regulation of SGLT1 by RS1 via Inhibition of ODC

Chakravarthi Chintalapati, Thorsten Keller, Thomas D. Mueller, Valentin Gorboulev, Nadine Schäfer, Ilona Zilkowski, Maike Veyhl-Wichmann, Dietmar Geiger, Jürgen Groll and Hermann Koepsell
Molecular Pharmacology November 1, 2016, 90 (5) 508-521; DOI: https://doi.org/10.1124/mol.116.104521

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Research ArticleArticle

Short-Term Regulation of SGLT1 by RS1 via Inhibition of ODC

Chakravarthi Chintalapati, Thorsten Keller, Thomas D. Mueller, Valentin Gorboulev, Nadine Schäfer, Ilona Zilkowski, Maike Veyhl-Wichmann, Dietmar Geiger, Jürgen Groll and Hermann Koepsell
Molecular Pharmacology November 1, 2016, 90 (5) 508-521; DOI: https://doi.org/10.1124/mol.116.104521
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