Astrocyte glutamate transporters

Removal of glutamate from the extracellular space is accomplished by specialized glutamate transporters expressed in both neurones and astroglial cells. Normal extracellular glutamate concentration varies between 2 and 5 ^M, reaching higher levels only for very brief moments at the peak of synaptic transmission. Intracellular glutamate concentration, in contrast, is much larger, being in the range of 1 to 10 mM. Therefore, removal of glutamate from the extracellular space requires transportation against a substantial concentration gradient. To perform this 'uphill' translocation, glutamate transporters utilize the transmembrane electrochemical gradients of Na+ and K+. Transport of a single glutamate molecule requires influx of three Na+ ions and efflux of one K+ ion, down their concentration gradients; in addition glutamate brings one more H+ ion into the cell (Figure 5.17). The net influx of cations manifests the electrogenic effect of glutamate transporters, which appears in a form of an inward current; the latter depolarizes the cell, further assisting the uptake of negatively charged glutamate.

There are five types of glutamate transporters in the human brain, classified as EAAT1 to EAAT5 (where EAAT stands for Excitatory Amino Acid Transporter), out of which EAAT1 and EAAT2 are expressed in astrocytes, and the remaining three types are expressed in various types of neurones. Analogues of EAAT1 and EAAT 2 expressed in rat brain are known as GLAST (glutamate/aspartate transporter) and GLT-1 (glutamate transporter-1), respectively. Functional properties of all transporters are similar, although they differ slightly in their binding affinities for glutamate.

Astroglial expression of glutamate transporters is tightly controlled by neighbouring neurones (or most likely by the continuous presence of glutamate released during neuronal synaptic transmission). Removal of glutamatergic transmission or loss of neurones causes a significant down-regulation of astroglial glutamate transporter expression.

Astrocyte Transporter

Figure 5.17 Ion fluxes generated by glutamate in glial cells and their relations to glutamate transport. Glutamate activates several molecular pathways and ion fluxes in astroglial cells. Glutamate activates ionotropic receptors and glutamate/Na+ (Glu/Na) transporters, which results in a net Na+ influx; the latter can increase intracellular Na+ concentration from the resting level of ~5 mM to 20-30 mM. This increase is counteracted by rapid reversal of the Na+/Ca2+ exchanger (NCX), which expels excess Na+ and provides Ca2+ entry, and a slower Na+ extrusion through the Na+/K+ pump, which is energy-dependent. Maintenance of low intracellular Na+ concentration is critically important for the performance of Na+/glutamate transporter and glutamate uptake

Figure 5.17 Ion fluxes generated by glutamate in glial cells and their relations to glutamate transport. Glutamate activates several molecular pathways and ion fluxes in astroglial cells. Glutamate activates ionotropic receptors and glutamate/Na+ (Glu/Na) transporters, which results in a net Na+ influx; the latter can increase intracellular Na+ concentration from the resting level of ~5 mM to 20-30 mM. This increase is counteracted by rapid reversal of the Na+/Ca2+ exchanger (NCX), which expels excess Na+ and provides Ca2+ entry, and a slower Na+ extrusion through the Na+/K+ pump, which is energy-dependent. Maintenance of low intracellular Na+ concentration is critically important for the performance of Na+/glutamate transporter and glutamate uptake

The performance of glutamate transporters clearly depends on the transmembrane concentration gradients for Na+ and K+ ; an increase in intracellular Na+ as well as an increase in extracellular K+ hamper glutamate transport. In this sense, the uptake of glutamate is highly energy dependent, since maintaining the Na+/K+ concentration gradients requires ATP to fuel Na+/K+ pumps. On average, transportation of a single glutamate molecule requires ~1.5 molecules of ATP. Quite naturally, therefore, ATP depletion and disruption of Na+/K+ home-ostasis, which inevitably accompany brain insults, inhibit astroglial glutamate uptake. Moreover, in certain conditions associated with severe energy deprivation and a significant increase in intracellular Na+, the transporter can reverse and deliver glutamate into the extracellular space, thus further exacerbating excitotox-icity. Importantly, astrocytes express relatively high densities of sodium-calcium exchangers (NCX), which, upon an increase in cytosolic Na+ concentration, are able to exchange Na+ for Ca2+ (known as the reverse mode of NCX); this process may rapidly lower [Na+]j, therefore maintaining the operation of glutamate transporters (Figure 5.17).

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