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Vol. 56, Issue 6, 1095-1104, December 1999
Departments of Pharmaceutical Sciences (H.P.K., R.J.B.) and
Chemistry (C.S.E.), University of Montana, Missoula, Montana;
Vollum Institute, Oregon Health Sciences University, Portland, Oregon
(M.P.K., N.Z., S.G.A.); Department of Chemistry, University of
California, Irvine, California (J.M.H., A.R.C.); and Howard Hughes
Medical Institute, Portland, Oregon (S.G.A.)
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-[3H]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.
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