Introduction to neurotransporters

Traditionally, synapses have been considered discrete information channels. This view has put great emphasis on the receptors and the release mechanisms, but has not given much room for a sophisticated role of transporters. The transporters have generally been considered essential, but relatively simple in that their task is to remove transmitter from the extracellular fluid. This view has now changed. The human genome contains about 500 different transporter protein genes, many of which are expressed in the nervous system. It is clear that transporters are more than passive players in signal transduction, but their precise roles still remain to be determined. Most of the transporters appear to be co-transporters catalyzing transport of both the substrate and accompanying ions. In addition, many of them display associated ion channel activities which are thermodynamically independent of the stoichiometric co-transport. The ion transport is likely to be functionally important because the transporters (e.g. the glutamate and system N transporters) are often expressed at high concentrations or highly select locations. Further, they are subject to sophisticated, but as yet poorly understood, regulation at all levels (DNA transcription, mRNA splicing and translation, protein modification and targeting, actual amino acid transport, and associated ion channel activities). Finally, transmitters, glutamate in particular, is continuously being released into the extracellular space by a variety of mechanisms and from a variety of sources (including glial cells), and the receptors (not least those for glutamate, of which there are many subtypes with widely different properties) are expressed in the plasma membranes of most of thecellular structures which make up brain tissue, and are thereby found both inside and outside of synapses (e.g. on nerve terminals, on dendritic spine necks, and even on glial cells). Consequently, control of transmitter concentrations and associated ion fluxes are important both outside and inside of synapses. Our main interest is glutamate and GABA transport and metabolism. Glutamate is fascinating because of the huge amounts of it in the brain, and the fact that it plays such essential roles memory, learning and cognition as well as for cell migration, survival and elimination. The nervous system expresses all the 5 different glutamate transporters (each of which may be subject to variable splicing), all of the 4 different GABA transporters, and both the glycine transporters. Disturbed control of extracellular glutamate appears to be an important factor, directly or indirectly, in all neurological disorders as well as in drug abuse and major psychiatric disorders (e.g. schizophrenia). This is a consequence of the abundance of glutamate, the ubiquitous presence of glutamate receptors, and the interplay between glutamate, oxidation and energy metabolism (for review see: Danbolt, 2001).

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