Tripeptides of RS1 (RSC1A1) inhibit a monosaccharide-dependent exocytotic pathway of Na+-D-glucose cotransporter SGLT1 with high affinity.
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 IC(50) 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-alpha-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.
Vernaleken
Alexandra
A
Institute of Anatomy and Cell Biology, University Würzburg, 97070 Würzburg, Germany.
Veyhl
Maike
M
Institute of Anatomy and Cell Biology, University Würzburg, 97070 Würzburg, Germany.
Gorboulev
Valentin
V
Institute of Anatomy and Cell Biology, University Würzburg, 97070 Würzburg, Germany.
Kottra
Gabor
G
Department of Food and Nutrition, Technical University Munich, 85350 Freising, Germany.
Palm
Dieter
D
Institute of Anatomy and Cell Biology, University Würzburg, 97070 Würzburg, Germany.
Burckhardt
Birgitta-Christina
BC
Institute of Physiology and Pathophysiology, University Göttingen, 37073 Göttingen, Germany.
Burckhardt
Gerhard
G
Institute of Physiology and Pathophysiology, University Göttingen, 37073 Göttingen, Germany.
Pipkorn
Rüdiger
R
German Cancer Research Center, 69120 Heidelberg, Germany.
Beier
Norbert
N
Diabetes Research Department of Merck KGaA, 64293 Darmstadt, Germany.
van Amsterdam
Christoph
C
Diabetes Research Department of Merck KGaA, 64293 Darmstadt, Germany.
Koepsell
Hermann
H
Institute of Anatomy and Cell Biology, University Würzburg, 97070 Würzburg, Germany. Electronic address: Hermann@Koepsell.de.
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D003847:Deoxyglucose / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D008757:Methylglucosides / Q000494:pharmacology; D009004:Monosaccharide Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009865:Oocytes / Q000166:cytology; D000074011:Peptide Transporter 1; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D021601:trans-Golgi Network / Q000378:metabolism
D000963:Antimetabolites; D008757:Methylglucosides; D009004:Monosaccharide Transport Proteins; D009842:Oligopeptides; D000074011:Peptide Transporter 1; C101014:RSC1A1 protein, human; C082186:SLC15A1 protein, human; C495674:SLC5A1 protein, human; C489940:Slc15a1 protein, rat; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D027981:Symporters; C027020:methylglucoside; D003847:Deoxyglucose; D005947:Glucose