Molecular characterization of substrate-binding sites in the glutamate transporter family

Glutamate transporters are essential for terminating synaptic excitation an d for maintaining extracellular glutamate concentrations below neurotoxic l evels. These transporters also mediate a thermodynamically uncoupled chlori de flux that is activated by two of the molecules that they transport - sod ium and glutamate. Five eukaryotic glutamate transporters have been cloned and identified. They exhibit similar to 50% identity and this homology is e ven greater in the carboxyl terminal half, which is predicted to have an un usual topology. Determination of the topology shows that the carboxyl termi nal part of the molecule contains several transmembrane domains that are se parated by at least two re-entrant loops. In these structural elements, we have identified several conserved amino acid residues that play crucial rol es in the interaction with the transporter substrates sodium, potassium and glutamate.