Differentiation of Substrate and Nonsubstrate Inhibitors of the High-Affinity, Sodium-Dependent

Within the mammalian central nervous system, the efficient removal of L-glutamate from the extracellular space by excita-tory 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 con-strained glutamate analogs to address two key issues: the differentiation of substrates from nontransportable inhibitors and the comparison of the pharmacological profile of synapto-somal uptake with those of the individual EAAT clones. We demonstrate that the process of transporter-mediated hetero