Serendipity: Discovery of the first glutamate neurotransmitter transporter GLAST-1 (EAAT-1) of CNS in excitatory neurotransmission and neurotoxicity.
L-Glutamate is the neurotransmitter of excitatory synapses in CNS. The glu concentration in the synaptic cleft is fine tuned by the orchestra of neurotransmitter glutamate release, glutamate receptors and Na+-dependent, high affinity (Km < 10 µM) glutamate uptake systems to prevent neuronal excitotoxicity. We have discovered the first CNS L-glutamate transporter GLAST1 (Glu-Asp-Transporter). Subsequently four more completed the family of Glu transporters: GLT1 (Pines et al.), EAAC1 (Kanai et al.), EAAT4 and EAAT5 (Arizza et al.). GLAST1 and GLT1 are expressed only in astrocytes, EAAC1 in neurons, kidney and jejunum. Different from the 12-TMD topology of the other neurotransmitter transporter topology, we characterized the membrane topology of the EAAT- family as an integral membrane protein with six TMD N-terminal domains followed by four ß-barrel C-terminal domains with the transport active site by "N-glycosylation scanning" (figure 2). We have generated and characterized the GLAST1 and EAAC1 single and GLAST1-EAAC1 deficient double mutant mouse models. Surprisingly these null mutants lacked the expected epileptic and neurotoxic phenotype. We have now focused on establishing the GLT1 deficient mouse model, because electrophysiological studies provided evidence that GLT1 is the "work horse", but GLAST1 and EAAC1 are the modulators of the glutamatergic synapse. An altered phenotype of the vestibular organ in GLAST-1 null mice has been described recently. Despite extensive biochemical and electrophysiological studies of these most important uptake systems, our knowledge of their individual role in vivo is still limited.
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