Astroglial glutamate transporters coordinate excitatory signaling and brain energetics

Abstract

In the mammalian brain, a family of sodium-dependent transporters maintains low extracellular glutamate and shapes excitatory signaling. The bulk of this activity is mediated by the astroglial glutamate transporters GLT-1 and GLAST (also called EAAT2 and EAAT1). In this review, we will discuss evidence that these transporters co-localize with, form physical (co-immunoprecipitable) interactions with, and functionally couple to various ‘energy-generating’ systems, including the Na+/K+-ATPase, the Na+/Ca2+ exchanger, glycogen metabolizing enzymes, glycolytic enzymes, and mitochondria/mitochondrial proteins. This functional coupling is bidirectional with many of these systems both being regulated by glutamate transport and providing the ‘fuel’ to support glutamate uptake. Given the importance of glutamate uptake to maintaining synaptic signaling and preventing excitotoxicity, it should not be surprising that some of these systems appear to ‘redundantly’ support the energetic costs of glutamate uptake. Although the glutamate-glutamine cycle contributes to recycling of neurotransmitter pools of glutamate, this is an over-simplification. The ramifications of co-compartmentalization of glutamate transporters with mitochondria for glutamate metabolism are discussed. Energy consumption in the brain accounts for ~20% of the basal metabolic rate and relies almost exclusively on glucose for the production of ATP. However, the brain does not possess substantial reserves of glucose or other fuels. To ensure adequate energetic supply, increases in neuronal activity are matched by increases in cerebral blood flow via a process known as ‘neurovascular coupling’. While the mechanisms for this coupling are not completely resolved, it is generally agreed that astrocytes, with processes that extend to synapses and endfeet that surround blood vessels, mediate at least some of the signal that causes vasodilation. Several studies have shown that either genetic deletion or pharmacologic inhibition of glutamate transport impairs neurovascular coupling. Together these studies strongly suggest that glutamate transport not only coordinates excitatory signaling, but also plays a pivotal role in regulating brain energetics.

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

“…Even if that is the case G DH might also play a role, possibly by supporting glutamate's cellular uptake, mediated by ion gradient-driven cotransport with Na + , which in the long run requires energyconsuming Na + ,K + -ATPase-mediated Na + extrusion. This is in agreement with the observation by Robinson and Jackson [102] that astrocytic glutamate transporters, mitochondrial enzymes and Na + ,K + -ATPase are co-localized and co-precipitate. These authors also suggest that glutamate transport (and thus presumably its subsequent intense metabolism [63]) plays an essential role in regulation of brain energetics.…”

Glutamine-Glutamate Cycle Flux Is Similar in Cultured Astrocytes and Brain and Both Glutamate Production and Oxidation Are Mainly Catalyzed by Aspartate Aminotransferase

“…Both Patel et al [113] and we ourselves [6] have debated reasons for the correlation between cycle flux and oxidative metabolism. The level of extracellular K + was found to regulate pyruvate carboxylation in cultured astrocytes [13] and high extracellular K + concentrations might activate glutamate synthesis, whereas the glutamate concentration is likely to regulate glutamate oxidation, at least within a certain range (determined by the K m and V max values for its uptake), as also concluded by Michael Robinson and coworkers [114]. Coupling between glutamate production and degradation will contribute to equalize fluxes from astrocytes to neurons and from neurons to astrocytes.…”

Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface

“…For instance, within the endfeetome, Myocilin [50, 51], Ptprz1 [52], the tissue plasminogen activator (tPA) [53] and the proteoglycan testican-2 (Spock2) [54] have all been shown to regulate neuronal architecture. The solute carriers Slc1a2 and Slc25a18 both promote glutamate transport at the plasma membrane and in the inner mitochondrial membrane respectively and might work in concert to regulate extra-synaptic level of glutamate and astrocyte energetic [55]. …”