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Differentiation of substrate and nonsubstrate inhibitors of the high-affinity, sodium-dependent glutamate transporters.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Koch, Hans Peter Kavanaugh, Michael P. Esslinger, Christoph Zerangue, Noa Humphrey, John M. Amara, Susan Gaye Chamberlin, A. Richard Bridges, Richard |
| Copyright Year | 1999 |
| Abstract | Within the mammalian central nervous system, the efficient removal of L-glutamate from the extracellular space by excitatory amino acid transporters (EAATs) has been postulated to contribute to signal termination, the recycling of transmitter, and the maintenance of L-glutamate at concentrations below those that are excitotoxic. The development of potent and selective inhibitors of the EAATs has contributed greatly to the understanding of the functional roles of these transporters. In the present study, we use a library of conformationally constrained glutamate analogs to address two key issues: the differentiation of substrates from nontransportable inhibitors and the comparison of the pharmacological profile of synaptosomal uptake with those of the individual EAAT clones. We demonstrate that the process of transporter-mediated heteroexchange can be exploited in synaptosomes to rapidly distinguish transportable from nontransportable inhibitors. Using this approach, we demonstrate that 2,4-methanopyrrolidine-2,4-dicarboxylate, cis-1-aminocyclobutane-1,3-dicarboxylate, and L-trans-2, 4-pyrrolidine dicarboxylate act as substrates for the rat forebrain synaptosomal glutamate uptake system. In contrast, L-anti-endo-3, 4-methanopyrrolidine-3,4-dicarboxylate, L-trans-2,3-pyrrolidine dicarboxylate, and dihydrokainate proved to be competitive inhibitors of D-[(3)H]aspartate uptake that exhibited little or no activity as substrates. When these same compounds were characterized for substrate activity by recording currents in voltage-clamped Xenopus laevis oocytes expressing the human transporter clones EAAT1, EAAT2, or EAAT3, it was found that the pharmacological profile of the synaptosomal system exhibited the greatest similarity with the EAAT2 subtype, a transporter believed to be expressed primarily on glial cells. |
| Starting Page | 183 |
| Ending Page | 188 |
| Page Count | 6 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://molpharm.aspetjournals.org/content/molpharm/56/6/1095.full.pdf |
| PubMed reference number | 10570036v1 |
| Volume Number | 56 |
| Issue Number | 6 |
| Journal | Molecular pharmacology |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 2,4-methanopyrrolidine-2,4-dicarboxylate Amino Acid Transporter Analog CNS disorder Cell Differentiation process Excitatory Amino Acids Extracellular Space Glutamic Acid Mammals Membrane Transport Proteins Neuroglia Pharmacology Prosencephalon SLC1A1 gene SLC1A2 wt Allele SLC1A3 gene Sodium Transmitter Device Component Xenopus laevis dicarboxylate dihydrokainate voltage |
| Content Type | Text |
| Resource Type | Article |
