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To maintain efficient synaptic communication, glutamate transporters reuptake glutamate from the synaptic cleft and prevent glutamate concentrations from reaching neurotoxic levels. The number of amino acid residues of the transmembrane (TM) domain 4b-4c loop of mammalian excitatory amino acid transporters (EAATs) is 50 amino acids more than that of the prokaryotic homolog. To investigate the spatial proximity and functional significance of residues in glutamate transporters, cysteine pairs were introduced at positions A243 of the TM4b-4c loop and T396 or A414 of TM7, respectively. The transport activity of double mutants A243C/T396C and A243C/A414C was inhibited by Cu(II) (1,10-phenanthroline) 3 [copper phenanthroline (CuPh)] and cadmium ions, but the uptake activity of corresponding single mutants remained unchanged. Treatment with dithiothreitol after CuPh restored much of the transport activity. The inhibitory effects of CuPh and cadmium could only be detected when cysteine pairs are in the same polypeptide. Therefore, we suggest that the formation of these disulfide bonds occurs intramolecularly. Glutamate, potassium, and DL- threo - β -benzyloxyaspartate facilitated crosslinking in the A243C/T396C transporter and this suggests that the TM4b-4c loop and β -bridge region in TM7 were drawn into close proximity to each other in the inward- and outward-facing conformation of EAAT1. Thus, these data provide evidence that substrate-induced structural rearrangements occur between the TM4b-4c loop and TM7 during the transport cycle.

Substrate-Induced Motion between TM4 and TM7 of the Glutamate Transporter EAAT1 Revealed by Paired Cysteine Mutagenesis