Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities

•New insights into the molecular dynamics of the EAAT transport cycle are reviewed.•Modes of action and properties of novel generations of EAAT modulators are outlined.•Recently identified physiological functions of EAATs are presented.

The five excitatory amino acid transporters (EAAT1–5) mediating the synaptic uptake of the major excitatory neurotransmitter glutamate are differently expressed throughout the CNS and at the synaptic level. Although EAATs are crucial for normal excitatory neurotransmission, explorations into the physiological functions mediated by the different transporter subtypes and their respective therapeutic potential have so far been sparse, in no small part due to the limited selection of pharmacological tools available. In the present update, we outline important new insights into the molecular compositions of EAATs and their intricate transport process, the novel approaches to pharmacological modulation of the transporters that have emerged, and interesting new perspectives in EAAT as drug targets proposed in recent years.