Characterization of the Tritium-Labeled Analog of L-<i>threo</i>-β-Benzyloxyaspartate Binding to Glutamate Transporters

Shimamoto, Keiko; Otsubo, Yasuto; Shigeri, Yasushi; Yasuda-Kamatani, Yoshimi; Satoh, Masamichi; Kaneko, Shuji; Nakagawa, Takayuki

doi:10.1124/mol.106.027250

Cited by 18 publications

(14 citation statements)

References 37 publications

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“…These types of studies showed that aspartate binding is coupled to the binding of at least two sodium ions, whereas the binding of TBOA is coupled to the binding of one sodium ion. The latter is consistent with the observation that binding of a radiolabeled TBOA analogue to eukaryotic glutamate transporters requires only one sodium ion (12). Moreover, the authors observed that lithium and thallium (Tl ϩ ), but not potassium, can substitute for sodium in the binding assay, albeit with a very low apparent affinity.…”

supporting

confidence: 85%

Gate Movements in Glutamate Transporters

Kanner

2007

ACS Chem. Biol.

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Sodium-coupled glutamate transporters are essential for efficient excitatory transmission in the brain and function by exposing their binding sites alternately to either the synapse or the interior of the cell. After the recent determination of the crystal structure of an archaeal homologue of the eukaryotic glutamate transporters, corresponding to the substrate occluded form, now the same has been achieved for the outwardfacing conformation. These structures provide important insights into the molecular mechanism of ion-coupled transporters.

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supporting

confidence: 85%

Gate Movements in Glutamate Transporters

Kanner

2007

ACS Chem. Biol.

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“…It has previously been demonstrated that 4MG, threo-3-methylglutamate, TBOA, and kainate are competitive blockers of EAAT2 (12,14,15), so K i values were calculated from IC 50 values using the Cheng-Prusoff equation (16).…”

Section: Expression Of Transporters In Xenopus Laevis Oocytes and Elementioning

confidence: 99%

The Role of Cation Binding in Determining Substrate Selectivity of Glutamate Transporters

Huang¹,

Ryan²,

Vandenberg

2009

Journal of Biological Chemistry

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Glutamate transport is coupled to the co-transport of 3Na ؉ and 1H؉ and the countertransport of 1 K ؉ . However, the mechanism of how this process occurs is not well understood. The crystal structure of an archaeal homolog of the human glutamate transporters, Glt Ph , has provided the framework to begin to understand the mechanism of transport. The glutamate transporter EAAT2 is different from other subtypes in two respects. First, Li ؉ cannot support transport by EAAT2, whereas it can support transport by the other excitatory amino acid transporters, and second, EAAT2 is sensitive to a wider range of blockers than other subtypes. We have investigated the relationship between the cation driving transport and whether the glutamate analogues, L-anti-endo-3,4-methanopyrrolidinedicarboxylic acid (MPDC) and (2S,4R)-4-methylglutamate (4MG), are substrates or blockers of transport. We have also investigated the molecular basis for these differences. EAAT2 has a Ser residue at position 441 with hairpin loop 2, whereas the corresponding residue in EAAT1 is a Gly residue. We demonstrate that if the transporter has a Ser residue at this position, then 4MG and MPDC are poor substrates in Na ؉ , and Li ؉ cannot support transport of any substrate. Conversely, if the transporter has a Gly residue at this position, then in Na ؉ 4MG and MPDC are substrates with efficacy comparable with glutamate, but in Li ؉ 4MG and MPDC are poor substrates relative to glutamate. This Ser/Gly residue is located between the bound substrate and one of the cation binding sites, which provides an explanation for the coupling of substrate and cation binding.

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“…Only a few inhibitors of EAAT4 or EAAT5 have been characterized in electrophysiological studies because the glutamate uptake capacities of these subtypes are much lower than those of EAAT1–3 63. Therefore, to develop a novel binding assay system for the evaluation of all EAAT subtypes, we synthesized a tritium‐labeled TBOA analog, [ 3 H]ETB‐TBOA ( 56 ) (Scheme ) 64. [ 3 H]ETB‐TBOA showed specific, high‐affinity binding to rat brain crude membranes or EAAT‐transfected COS‐1 cell membranes expressing each EAAT subtype.…”

Section: Syntheses Of Functionalized Tboa Derivativesmentioning

confidence: 99%

The mother of turf wars: Carotid stents

White¹

2004

Cathet Cardio Intervent

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Characterization of the Tritium-Labeled Analog of L-threo-β-Benzyloxyaspartate Binding to Glutamate Transporters

Cited by 18 publications

References 37 publications

Gate Movements in Glutamate Transporters

Gate Movements in Glutamate Transporters

The Role of Cation Binding in Determining Substrate Selectivity of Glutamate Transporters

The mother of turf wars: Carotid stents

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