Milestone Review: Excitatory amino acid transporters - Beyond their expected function.

Glutamate is the major excitatory neurotransmitter in the vertebrate brain, it is critically involved in the function and dysfunction of the central nervous system. The molecular cloning of its ionotropic receptors in the last decade of the past century increased exponentially the interest in this neurotransmitter system. Since then, a plethora of knowledge of the structure, function, and regulation of its receptors and transporters has advanced our understanding of glutamate-mediated neurochemical transactions. Moreover, the characterization of glial glutamate receptors together with the compulsory participation of surrounding astrocytes in glutamate turnover and in the known metabolic coupling with neurons has supported what is now known as the tripartite synapses. The molecular characterization of the various glutamate transporters has also been fundamental for the involvement of glial cells in glutamatergic synapses. Using radial glial cultures, over the years, we have demonstrated an alternative glutamate-mediated signaling system triggered by sodium-dependent glutamate transporters. A detailed account of these findings and the signaling through other glutamate transporters are presented here. The role of this signaling system in the context of glutamatergic transmission is discussed as well as the future directions in the field.