Glutamate Transporters

A hallmark of many neurodegenerative diseases is the disruption of normal glutamate metabolism. For example, in amyotrophic lateral sclerosis about a third of patients have lost more than 90% of their EAAT2 transporters and another third have lost 40-50% of their EAAT2 transporters. Fewer transporters results in higher levels of synaptic glutamate. And, in fact, glutamate is present in elevated concentrations in neurodegenerative diseases. Excess glutamate in turn activates glutamate receptors to levels above basal neurotransmission, which leads to the initiation of neurotoxic signaling cascades leading to cell death.

Ruxton’s approach is to increase the number of glutamate transporters during disease. By overcoming the initial loss of these proteins, we have demonstrated in vitro the ability to remove excess glutamate from the synaptic cleft and in animals the ability to protect cells from neurodegeneration. Five distinct cDNA clones that express sodium-dependent high-affinity glutamate transporters have been isolated and named:

Of the four transporters found in forebrain (all but EAAT5), EAAT2 and EAAT4 appear to be largely specific to brain tissue. Here is a diagrammatic representation of the localization of these transporters: