TY - JOUR T1 - A Modified Tripeptide Motif of RS1 (<em>RSC1A1</em>) Downregulates Exocytotic Pathways of Human Na<sup>+</sup>-D-glucose Cotransporters SGLT1, SGLT2 and Glucose Sensor SGLT3 in the Presence of Glucose. JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.118.113514 SP - mol.118.113514 AU - Nadine Schafer AU - Prashanth Reddy Rikkala AU - Maike Veyhl-Wichmann AU - Thorsten Keller AU - Christian Ferdinand Jurowich AU - Dietmar Geiger AU - Hermann Koepsell Y1 - 2018/01/01 UR - http://molpharm.aspetjournals.org/content/early/2018/10/24/mol.118.113514.abstract N2 - A domain of protein RS1 (RSC1A1) termed RS1-Reg downregulates 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 motif is replaced by glutamate (RS1-Reg(S20E)). RS1-Reg binds to ornithine decarboxylase (ODC) and inhibits ODC in a glucose-dependent manner. Because 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) downregulates the exocytotic pathway of SGLT1 at the trans-Golgi by inhibiting ODC. We investigated whether QEP downregulates 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 α-methyl-D-glucopyranoside (AMG), and measured AMG uptake, glucose-induced currents and plasma membrane-associated fluorescence after one hour. We also performed in vitro AMG uptake measurements into small intestinal mucosa of mice and human. The data indicate that QEP downregulates the exocytotic pathway of SGLT1 similar to hRS1-Reg(S20E). They suggest that both peptides also downregulate hSGLT2 and hSGLT3 via the same pathway. Thirty min 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 40-50%. Oral application of QEP in a formulation that optimizes uptake into enterocytes but prevents entry into the blood, is proposed as novel antidiabetic therapy. ER -