%0 Journal Article %1 schafer2019modified %A Schafer, N. %A Rikkala, P. R. %A Veyhl-Wichmann, M. %A Keller, T. %A Jurowich, C. F. %A Geiger, D. %A Koepsell, H. %D 2019 %J Mol Pharmacol %K Adult myOwn %N 1 %P 82-96 %R 10.1124/mol.118.113514 %T A Modified Tripeptide Motif of RS1 (RSC1A1) Down-Regulates Exocytotic Pathways of Human Na(+)-d-glucose Cotransporters SGLT1, SGLT2, and Glucose Sensor SGLT3 in the Presence of Glucose %U https://www.ncbi.nlm.nih.gov/pubmed/30355744 %V 95 %X A domain of protein RS1 (RSC1A1) called RS1-Reg down-regulates the plasma membrane abundance of Na(+)-d-glucose cotransporter SGLT1 by blocking the exocytotic pathway at the trans-Golgi. This effect is blunted by intracellular glucose but prevails when serine in a QSP (Gln-Ser-Pro) motif is replaced by glutamate RS1-Reg(S20E). RS1-Reg binds to ornithine decarboxylase (ODC) and inhibits ODC in a glucose-dependent manner. Because the ODC inhibitor difluoromethylornithine (DFMO) acts like RS1-Reg(S20E), and DFMO and RS1-Reg(S20E) are not cumulative, we raised the hypothesis that RS1-Reg(S20E) down-regulates the exocytotic pathway of SGLT1 at the trans-Golgi by inhibiting ODC. We investigated whether QEP down-regulates human SGLT1 (hSGLT1) like hRS1-Reg(S20E) and whether human Na(+)-d-glucose cotransporter hSGLT2 and the human glucose sensor hSGLT3 are also addressed. We expressed hSGLT1, hSGLT1 linked to yellow fluorescent protein (hSGLT1-YFP), hSGLT2-YFP and hSGLT3-YFP in oocytes of Xenopus laevis, injected hRS1-Reg(S20E), QEP, DFMO, and/or alpha-methyl-d-glucopyranoside (AMG), and measured AMG uptake, glucose-induced currents, and plasma membrane-associated fluorescence after 1 hour. We also performed in vitro AMG uptake measurements into small intestinal mucosa of mice and human. The data indicate that QEP down-regulates the exocytotic pathway of SGLT1 similar to hRS1-Reg(S20E). Our results suggests that both peptides also down-regulate hSGLT2 and hSGLT3 via the same pathway. Thirty minutes after application of 5 mM QEP in the presence of 5 mM d-glucose, hSGLT1-mediated AMG uptake into small intestinal mucosa was decreased by 40% to 50%. Thus oral application of QEP in a formulation that optimizes uptake into enterocytes but prevents entry into the blood is proposed as novel antidiabetic therapy.

@article{schafer2019modified, abstract = {A domain of protein RS1 (RSC1A1) called RS1-Reg down-regulates the plasma membrane abundance of Na(+)-d-glucose cotransporter SGLT1 by blocking the exocytotic pathway at the trans-Golgi. This effect is blunted by intracellular glucose but prevails when serine in a QSP (Gln-Ser-Pro) motif is replaced by glutamate [RS1-Reg(S20E)]. RS1-Reg binds to ornithine decarboxylase (ODC) and inhibits ODC in a glucose-dependent manner. Because the ODC inhibitor difluoromethylornithine (DFMO) acts like RS1-Reg(S20E), and DFMO and RS1-Reg(S20E) are not cumulative, we raised the hypothesis that RS1-Reg(S20E) down-regulates the exocytotic pathway of SGLT1 at the trans-Golgi by inhibiting ODC. We investigated whether QEP down-regulates human SGLT1 (hSGLT1) like hRS1-Reg(S20E) and whether human Na(+)-d-glucose cotransporter hSGLT2 and the human glucose sensor hSGLT3 are also addressed. We expressed hSGLT1, hSGLT1 linked to yellow fluorescent protein (hSGLT1-YFP), hSGLT2-YFP and hSGLT3-YFP in oocytes of Xenopus laevis, injected hRS1-Reg(S20E), QEP, DFMO, and/or alpha-methyl-d-glucopyranoside (AMG), and measured AMG uptake, glucose-induced currents, and plasma membrane-associated fluorescence after 1 hour. We also performed in vitro AMG uptake measurements into small intestinal mucosa of mice and human. The data indicate that QEP down-regulates the exocytotic pathway of SGLT1 similar to hRS1-Reg(S20E). Our results suggests that both peptides also down-regulate hSGLT2 and hSGLT3 via the same pathway. Thirty minutes after application of 5 mM QEP in the presence of 5 mM d-glucose, hSGLT1-mediated AMG uptake into small intestinal mucosa was decreased by 40% to 50%. Thus oral application of QEP in a formulation that optimizes uptake into enterocytes but prevents entry into the blood is proposed as novel antidiabetic therapy.}, added-at = {2024-02-15T15:08:22.000+0100}, author = {Schafer, N. and Rikkala, P. R. and Veyhl-Wichmann, M. and Keller, T. and Jurowich, C. F. and Geiger, D. and Koepsell, H.}, biburl = {https://www.bibsonomy.org/bibtex/2af1fdf1271c6d48d2f1d62e80420b2a9/jvsi_all}, doi = {10.1124/mol.118.113514}, interhash = {30a9ae32029e2e95b6e7f4c6519138de}, intrahash = {af1fdf1271c6d48d2f1d62e80420b2a9}, issn = {1521-0111 (Electronic) 0026-895X (Linking)}, journal = {Mol Pharmacol}, keywords = {Adult myOwn}, note = {Schafer, Nadine Rikkala, Prashanth Reddy Veyhl-Wichmann, Maike Keller, Thorsten Jurowich, Christian Ferdinand Geiger, Dietmar Koepsell, Hermann eng Research Support, Non-U.S. Gov't 2018/10/26 Mol Pharmacol. 2019 Jan;95(1):82-96. doi: 10.1124/mol.118.113514. Epub 2018 Oct 24.}, number = 1, pages = {82-96}, timestamp = {2024-02-15T15:08:22.000+0100}, title = {A Modified Tripeptide Motif of RS1 (RSC1A1) Down-Regulates Exocytotic Pathways of Human Na(+)-d-glucose Cotransporters SGLT1, SGLT2, and Glucose Sensor SGLT3 in the Presence of Glucose}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/30355744}, volume = 95, year = 2019 }