Glutamate transporters serve the important function of mediating removal of 
glutamate released at excitatory synapses and maintaining extracellular 
concentrations below excitotoxic levels. Excitatory amino acid transporter 
subtypes EAAT1 and EAAT2 have a high degree of sequence homology and similar 
predicted topology and yet display a number of functional differences. Several 
recombinant chimeric transporters were generated to identify domains that 
contribute to functional differences between EAAT1 and EAAT2. Wild-type 
transporters and chimeric transporters were expressed in Xenopus laevis oocytes, 
and electrogenic transport was studied under voltage clamp conditions. The 
differential sensitivity of EAAT1 and EAAT2 to transport blockers, kainate, 
threo-3-methylglutamate, and (2S, 4R)-4-methylglutamate as well as 
L-serine-O-sulfate transport and chloride permeability were employed to 
characterize chimeric transporters. One particular region, transmembrane domains 
9 and 10, plays an important role in defining these functional differences. The 
intracellular carboxyl-terminal region may also play a minor role in conferring 
an effect on chloride permeability. This study provides important insight into 
the identification of functional domains that determine differences among 
glutamate transporter subtypes.