Vesicular glutamate transporters in the brain

Glutamate is an excitatory amino acid that acts as a major neurotransmitter throughout the brain. Although its neurotransmitter action has been evidenced by the identification of various receptor subtypes at synapses, a cellular mechanism by which this amino acid accumulates in synaptic vesicles has long been in doubt until the discovery in recent years of specific vesicular transporters. Three kinds of transporter isoforms have so far been cloned and their transport properties and distribution in the brain have been studied extensively. In contrast with the apparently similar ability of all transporter isoforms to highly selectively transport glutamate and their presence in synaptic vesicles, their regional distribution of gene expression and immunoreactivity in the rodent or human brain are surprisingly different from one another. This indicates that the glutamatergic neuron system of mammalian brains is substantially comprised of at least three different neuron subpopulations, each of which uses a unique transport system for the vesicular storage of glutamate. Thus, we now have highly useful and reliable tools for a comprehensive understanding of the glutamatergic neuron system in the brain from a new viewpoint different from that of other components, such as receptors. The scope of the present review is to provide an overview of the history and present status of the study of vesicular glutamate transporters and to highlight some unresolved issues requiring clarification for the progress of future brain function research.