Structural and functional dynamics of Excitatory Amino Acid Transporters (EAAT)

Glutamate transporters control the glutamate homeostasis in the central nervous system, and, thus, are not only crucial for physiological excitatory synaptic signaling, but also for the prevention of a large number of neurodegenerative diseases that are associated with excessive and prolonged presence of the neurotransmitter glutamate in the extracellular space. Until now, five subtypes of high-affinity glutamate transporters (excitatory amino acid transporters, EAATs 1–5) have been identified. These 5 high-affinity glutamate transporter subtypes belong to the solute carrier 1 (SLC1) family of transmembrane proteins: EAAT1/GLAST (SLC1A3), EAAT2/GLT1 (SLC1A2), EAAT3/EAAC1 (SLC1A1), EAAT4 (SLC1A6) and EAAT5 (SLC1A7). EAATs are secondary-active transporters, taking up glutamate into the cell against a substantial concentration gradient. The driving force for concentrative uptake is provided by the co-transport of Na+ ions and the counter-transport of one K+ in a step independent of the glutamate translocation step. Due to the electrogenicity of transport, the transmembrane potential can also act as driving force. Glutamate transporters are also able to run in reverse, resulting in glutamate release from cells. Due to these important physiological functions, glutamate transporter expression and, therefore, the transport rate, are tightly regulated. The EAAT protein family are structurally expected to be highly similar, however, these transporters show a functional diversity that ranges from high capacity glutamate uptake systems (EAATs 1–3) to receptor-like glutamate activated anion channels (EAATs 4–5). Here, we provide an update on most recent progress made on EAAT’s molecular transport mechanism, structure-function relationships, pharmacology, and will add recent insights into mechanism of rapid membrane trafficking of glutamate transporters.