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J Membr Biol
2008 May 01;2232:87-106. doi: 10.1007/s00232-008-9116-6.
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How drugs interact with transporters: SGLT1 as a model.
Loo DD
,
Hirayama BA
,
Sala-Rabanal M
,
Wright EM
.
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Drugs are transported by cotransporters with widely different turnover rates. We have examined the underlying mechanism using, as a model system, glucose and indican (indoxyl-beta-D-glucopyranoside) transport by human Na+/glucose cotransporter (hSGLT1). Indican is transported by hSGLT1 at 10% of the rate for glucose but with a fivefold higher apparent affinity. We expressed wild-type hSGLT1 and mutant G507C in Xenopus oocytes and used electrical and optical methods to measure the kinetics of glucose (using nonmetabolized glucose analogue alpha-methyl-D-glucopyranoside, alphaMDG) and indican transport, alone and together. Indican behaved as a competitive inhibitor of alphaMDG transport. To examine protein conformations, we recorded SGLT1 capacitive currents (charge movements) and fluorescence changes in response to step jumps in membrane voltage, in the presence and absence of indican and/or alphaMDG. In the absence of sugar, voltage jumps elicited capacitive SGLT currents that decayed to steady state with time constants (tau) of 3-20 ms. These transient currents were abolished in saturating alphaMDG but only slightly reduced (10%) in saturating indican. SGLT1 G507C rhodamine fluorescence intensity increased with depolarizing and decreased with hyperpolarizing voltages. Maximal fluorescence increased approximately 150% in saturating indican but decreased approximately 50% in saturating alphaMDG. Modeling indicated that the rate-limiting step for indican transport is sugar translocation, whereas for alphaMDG it is dissociation of Na+ from the internal binding sites. The inhibitory effects of indican on alphaMDG transport are due to its higher affinity and a 100-fold lower translocation rate. Our results indicate that competition between substrates and drugs should be taken into consideration when targeting transporters as drug delivery systems.
Bezanilla,
The voltage sensor in voltage-dependent ion channels.
2000, Pubmed
Bezanilla,
The voltage sensor in voltage-dependent ion channels.
2000,
Pubmed
Birnir,
Voltage-clamp studies of the Na+/glucose cotransporter cloned from rabbit small intestine.
1991,
Pubmed
,
Xenbase
Briasoulis,
Phase I trial of 6-hour infusion of glufosfamide, a new alkylating agent with potentially enhanced selectivity for tumors that overexpress transmembrane glucose transporters: a study of the European Organization for Research and Treatment of Cancer Early Clinical Studies Group.
2000,
Pubmed
Díez-Sampedro,
Glycoside binding and translocation in Na(+)-dependent glucose cotransporters: comparison of SGLT1 and SGLT3.
2000,
Pubmed
,
Xenbase
Díez-Sampedro,
Residue 457 controls sugar binding and transport in the Na(+)/glucose cotransporter.
2001,
Pubmed
,
Xenbase
Eskandari,
Kinetics of the reverse mode of the Na+/glucose cotransporter.
2005,
Pubmed
,
Xenbase
Falk,
Reduction of an eight-state mechanism of cotransport to a six-state model using a new computer program.
1998,
Pubmed
Hazama,
Presteady-state currents of the rabbit Na+/glucose cotransporter (SGLT1).
1997,
Pubmed
,
Xenbase
Hirayama,
Kinetic and specificity differences between rat, human, and rabbit Na+-glucose cotransporters (SGLT-1).
1996,
Pubmed
,
Xenbase
Hirayama,
Cation effects on protein conformation and transport in the Na+/glucose cotransporter.
1997,
Pubmed
,
Xenbase
Hirayama,
Sodium-dependent reorganization of the sugar-binding site of SGLT1.
2007,
Pubmed
,
Xenbase
Hirayama,
Common mechanisms of inhibition for the Na+/glucose (hSGLT1) and Na+/Cl-/GABA (hGAT1) cotransporters.
2001,
Pubmed
,
Xenbase
King,
Nucleoside transporters: from scavengers to novel therapeutic targets.
2006,
Pubmed
Knütter,
Synthesis and characterization of a new and radiolabeled high-affinity substrate for H+/peptide cotransporters.
2007,
Pubmed
,
Xenbase
Larráyoz,
Electrophysiological characterization of the human Na(+)/nucleoside cotransporter 1 (hCNT1) and role of adenosine on hCNT1 function.
2004,
Pubmed
Loewen,
Transport of physiological nucleosides and anti-viral and anti-neoplastic nucleoside drugs by recombinant Escherichia coli nucleoside-H(+) cotransporter (NupC) produced in Xenopus laevis oocytes.
2004,
Pubmed
,
Xenbase
Loo,
Conformational changes couple Na+ and glucose transport.
1998,
Pubmed
,
Xenbase
Loo,
Perturbation analysis of the voltage-sensitive conformational changes of the Na+/glucose cotransporter.
2005,
Pubmed
,
Xenbase
Loo,
Passive water and ion transport by cotransporters.
1999,
Pubmed
,
Xenbase
Loo,
Relaxation kinetics of the Na+/glucose cotransporter.
1993,
Pubmed
,
Xenbase
Loo,
Conformational dynamics of hSGLT1 during Na+/glucose cotransport.
2006,
Pubmed
,
Xenbase
Lostao,
Phenylglucosides and the Na+/glucose cotransporter (SGLT1): analysis of interactions.
1994,
Pubmed
,
Xenbase
Mackenzie,
Relationships between Na+/glucose cotransporter (SGLT1) currents and fluxes.
1998,
Pubmed
,
Xenbase
Mackey,
Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters.
1999,
Pubmed
,
Xenbase
Meinild,
Fluorescence studies of ligand-induced conformational changes of the Na(+)/glucose cotransporter.
2002,
Pubmed
,
Xenbase
Parent,
Electrogenic properties of the cloned Na+/glucose cotransporter: II. A transport model under nonrapid equilibrium conditions.
1992,
Pubmed
Quick,
Neutralization of a conserved amino acid residue in the human Na+/glucose transporter (hSGLT1) generates a glucose-gated H+ channel.
2001,
Pubmed
,
Xenbase
Sala-Rabanal,
Molecular interactions between dipeptides, drugs and the human intestinal H+ -oligopeptide cotransporter hPEPT1.
2006,
Pubmed
,
Xenbase
Sala-Rabanal,
Molecular mechanism of dipeptide and drug transport by the human renal H+/oligopeptide cotransporter hPEPT2.
2008,
Pubmed
,
Xenbase
Smith,
Electrophysiological characterization of a recombinant human Na+-coupled nucleoside transporter (hCNT1) produced in Xenopus oocytes.
2004,
Pubmed
,
Xenbase
Veenstra,
Local conformational changes in the Vibrio Na+/galactose cotransporter.
2004,
Pubmed
Veyhl,
Transport of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na+-D-glucose cotransporter SAAT1.
1998,
Pubmed
,
Xenbase
Yao,
Transport of adenosine by recombinant purine- and pyrimidine-selective sodium/nucleoside cotransporters from rat jejunum expressed in Xenopus laevis oocytes.
1996,
Pubmed
,
Xenbase
Zampighi,
A method for determining the unitary functional capacity of cloned channels and transporters expressed in Xenopus laevis oocytes.
1995,
Pubmed
,
Xenbase
