The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms

High-affinity glutamate transporters ensure termination of glutamatergic ne urotransmission and keep the synaptic concentration of this: amino :acid be low excitotoxic levels. However, neuronal glutamate transporters, EAAC1 and EAAT4, are located outside the synaptic cleft and contribute less signific antly to the glutamate uptake in the brain than two astroglial transporters , GLAST and GLT1. Aberrant functioning of the glutamate uptake system seems to be linked to some neurodegenerative disorders (eg amyotrophic lateral s clerosis, ALS). Expression of glutamate transporters is differentially regu lated via distinct cellular mechanisms. CLT1, which is expressed at very lo w levels in cultured astrocytes, is strongly induced in the presence of neu rons. The presence immunocytochemical data provide further evidence that ne uronal soluble factors, rather than physical contact between neurons and gl ia, determine the induction of GLT1 in astrocytes. This effect is apparentl y mediated by yet undefined growth factors(s) via the tyrphostin-sensitive receptor tyrosine kinase (RTK) signalling, that in turn, supports the downs tream activation of p42/44 MAP kinases and the CREM and ATF-1 transcription factors. RTK-independent simultaneous activation of the CREB transcription factor suggests a possible involvement of complementary pathway(s). Neuron al soluble factors do not affect expression of GLAST, but induce supporting machinery for differential regulation of GLAST via the astroglial motabotr opic glutamate receptors, mGluR3 and mGluR5. Thus, long-term treatment with the group I mGluR agonist, DHPG, causes down-regulation of GLAST, whereas the group II agonist, DCG-IV, has an opposite effect on the expression of G LAST in astrocytes. However, in BT4C glioma cells glutamate or other transp ortable substrates (D-aspartate and L-2,4-trans-PDC) induced cell-surface e xpression of EAAT4 in a receptor-independent manner. The activity-dependent trafficking of this transporter which also exhibits properties of a glutam ate-gated chloride channel may play functional roles not only in neuronal e xcitability, but in glioma cell biology as well. (C) 2000 Elsevier Science Ltd. All rights reserved.