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J. Biol. Chem., Vol. 282, Issue 39, 28501-28513, September 28, 2007

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Tripeptides of RS1 (RSC1A1) Inhibit a Monosaccharide-dependent Exocytotic Pathway of Na⁺-D-Glucose Cotransporter SGLT1 with High Affinity^*

Alexandra Vernaleken¹, Maike Veyhl¹, Valentin Gorboulev, Gabor Kottra, Dieter Palm, Birgitta-Christina Burckhardt^¶, Gerhard Burckhardt^¶, Rüdiger Pipkorn^||, Norbert Beier^**, Christoph van Amsterdam^**, and Hermann Koepsell²

From the Institute of Anatomy and Cell Biology, University Würzburg, 97070 Würzburg, Germany, the Department of Food and Nutrition, Technical University Munich, 85350 Freising, Germany, the ^¶Institute of Physiology and Pathophysiology, University Göttingen, 37073 Göttingen, Germany, the ^||German Cancer Research Center, 69120 Heidelberg, Germany, and the ^**Diabetes Research Department of Merck KGaA, 64293 Darmstadt, Germany

The human gene RSC1A1 codes for a 67-kDa protein named RS1 that mediates transcriptional and post-transcriptional regulation of Na⁺-D-glucose cotransporter SGLT1. The post-transcriptional regulation occurs at the trans-Golgi network (TGN). We identified two tripeptides in human RS1 (Gln-Cys-Pro (QCP) and Gln-Ser-Pro (QSP)) that induce posttranscriptional down-regulation of SGLT1 at the TGN leading to 40–50% reduction of SGLT1 in plasma membrane. For effective intracellular concentrations IC₅₀ values of 2.0 nM (QCP) and 0.16 nM (QSP) were estimated. Down-regulation of SGLT1 by tripeptides was attenuated by intracellular monosaccharides including non-metabolized methyl--D-glucopyranoside and 2-deoxyglucose. In small intestine post-transcriptional regulation of SGLT1 may contribute to glucose-dependent regulation of liver metabolism and intestinal mobility. QCP and QSP are transported by the H⁺-peptide cotransporter PepT1 that is colocated with SGLT1 in small intestinal enterocytes. Using coexpression of SGLT1 and PepT1 in Xenopus oocytes or polarized Caco-2 cells that contain both transporters we demonstrated that the tripeptides were effective when applied to the extracellular compartment. After a 1-h perfusion of intact rat small intestine with QSP, glucose absorption was reduced by 30%. The data indicate that orally applied tripeptides can be used to down-regulate small intestinal glucose absorption, e.g. in diabetes mellitus.

Received for publication, July 2, 2007 , and in revised form, August 3, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 487/C1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the work.

² To whom correspondence should be addressed: Institute of Anatomy and Cell Biology, Koellikerstr. 6, 97070 Würzburg, Germany. Tel.: 49-931-312700; Fax: 49-931-312087; E-mail: Hermann{at}Koepsell.de.

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