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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Glutamate Transporters

and .

Correspondence to Raymond Dingledine, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322-3090.

As zwitterionic molecules, glutamate and aspartate are unable to diffuse across membranes. It is now well documented that uptake mechanisms have an important role in regulating the extracellular concentrations of glutamate and aspartate in the brain. At least two families of glutamate transporter have been localized to the plasma membrane of neurons and astrocytes (Fig. 15-7). Only the Na+-dependent glutamate transporter is coupled to the electrochemical gradient that permits transport of glutamate and aspartate against their concentration gradients. To date, four members of the Na+-dependent glutamate transporter family have been cloned [25]. Na+-dependent glutamate transporters transport l-aspartate and l-glutamate with similar apparent affinity and maximum velocity. Unlike many of the other CNS transport systems, this process transports d-aspartate with similar affinity but does not transport d-glutamate.

Three members of this family have been cloned to date: the glutamate—aspartate transporter (GLAST), glutamate transporter-1 (GLT-1) and excitatory amino acid carrier-1 (EAAC1). Human orthologs of these three transporters also have been cloned (EAAT1, EAAT2 and EAAT3). Another member of this family, EAAT4, was cloned from human motor cortex. The glutamate transporters share little or no sequence similarity with other Na+-dependent transporters, such as those for norepinephrine, dopamine, GABA and serotonin, and therefore, are members of a new gene family. The predicted amino acid sequences of the three proteins share ~50% homology with one another.

In the CNS, GLT-1 and GLAST are expressed preferentially in glial cells. GLT-1 has its highest expression in the thalamus and cerebellum, with lower levels in the hippocampus, cortex and striatum. GLAST immunoreactivity is found predominantly in the cerebellum and less so in the forebrain. In contrast, EAAC1 is expressed predominantly in neurons, most prominently in the hippocampus, and is absent from glial cells. The expression patterns of the three members of this family, therefore, suggest that GLT-1 and GLAST represent the primary transport carrier for glutamate uptake into glia, while EAAC1 is involved predominantly in neuronal glutamate and aspartate uptake (Fig. 15-7). Na+-dependent glutamate transporters, unlike other amine transporters, are not C1-dependent. The net transport of glutamate is increased by high intracellular K+; upon dissociation of glutamate and Na+ from the transport machinery, cytoplasmic K+ binds to be recycled into the extracellular compartment. With each cycle, two Na+ ions accompany the movement of glutamate or aspartate into the intracellular compartment, with one K+ ion being transported out, accompanied by either OH or HCO3. Therefore, one complete cycle results in a net positive movement of charge into the cell.

A major role for glutamate transporters is to limit the free concentrations of glutamate and aspartate in the extracellular space, thus preventing excessive stimulation of glutamate receptors [26]. It is likely that membrane depolarization during ischemic insult causes reverse transport of glutamate, or aspartate, out of glia and/or neurons. Accumulation of aspartate or glutamate in the extracellular space and the resulting excessive activation of glutamate receptors can result in a number of pathological conditions and, ultimately, cell death.

Image ch15f7

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK27931

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