GLAST/EAAT1-induced Glutamine release via SNAT3 in Bergmann glial cells: evidence of a functional and physical coupling (original) (raw)

The Glia Connection of the Glutamate/Glutamine Shuttle

Problem statement: Glia cells outnumber neurons but their role in synaptic transmission is still matter of debate. The recycling of Glutamate, the main excitatory neurotransmitter, carried out by the glutamate/glutamine shuttle, requires the involvement of glia, suggesting their involvement in neurotransmission. Approach: This review focuses on novel functions of glia proteins involved in this cycle. Results: An activity-dependent interaction of glial glutamate transporters, the Na +/K+ ATPase, the glutamine and glucose transporters might support glutamatergic neurotransmission. Conclusion: Glia cells that surround glutamatergic contacts, respond to synaptic activity and modify accordingly, the amount and function of the proteins involved in their interaction with neurons thus assuring a synaptic transmission.

Glial glutamate transporters: New actors in brain signaling

IUBMB Life, 2011

Glutamate, the main excitatory amino acid in the vertebrate brain, is critically involved in most of the physiological functions of the central nervous system. It has traditionally been assumed that glutamate triggers a wide array of signaling cascades through the activation of specific membrane receptors. The extracellular levels are tightly regulated to prevent neurotoxic insults. Electrogenic Na 1 -dependent glial glutamate transporters remove the bulk of the neurotransmitter from the synaptic cleft. An exquisitely ordered coupling between glutamatergic neurons and surrounding glia cells is fundamental for excitatory transmission. The glutamate/glutamine and astrocyte/ neuron lactate shuttles provide the biochemical framework of this compulsory association. In this context, recent advances show that glial glutamate transporters act as signal transducers that regulate the expression of proteins involved in their compartmentalization with neurons in the so-called tripartite synapse.

Glutamate Receptor Stimulation Up-Regulates Glutamate Uptake in Human Müller Glia Cells

Neurochemical Research, 2016

Glutamate, the main excitatory amino acid in the vertebrate retina, is a well know activator of numerous signal transduction pathways, and has been critically involved in long-term synaptic changes acting through ionotropic and metabotropic glutamate receptors. However, recent findings underlining the importance of intensity and duration of glutamate stimuli for specific neuronal responses, including excitotoxicity, suggest a crucial role for Na ?-dependent glutamate transporters, responsible for the removal of this neurotransmitter from the synaptic cleft, in the regulation of glutamate-induced signaling. Transporter proteins are expressed in neurons and glia cells, albeit most of glutamate uptake occurs in the glial compartment. Within the retina, Müller glia cells are in close proximity to glutamatergic synapses and participate in the recycling of glutamate through the glutamate/glutamine shuttle. In this context, we decided to investigate a plausible role of glutamate as a regulatory signal for its own transport in human retinal glia cells. To this end, we determined [ 3 H]-D-aspartate uptake in cultures of spontaneously immortalized human Müller cells (MIO-M1) exposed to distinct glutamatergic ligands. A time and dosedependent increase in the transporter activity was detected. This effect was dependent on the activation of the Nmethyl D-aspartate subtype of glutamate receptors, due to a dual effect: an increase in affinity and an augmented expression of the transporter at the plasma membrane, as established via biotinylation experiments. Furthermore, a NMDA-dependent association of glutamate transporters with the cystoskeletal proteins ezrin and glial fibrillary acidic protein was also found. These results add a novel mediator of the glutamate transporter modulation and further strengthen the notion of the critical involvement of glia cells in synaptic function.

Glutamate-mediated neuronal?glial transmission

Journal of Anatomy, 2007

The brain is the most complex organ of the human body. It is composed of several highly specialized and heterogeneous populations of cells, represented by neurones (e.g. motoneurons, projection neurons or interneurons), and glia represented by astrocytes, oligodendrocytes and microglia. In recent years there have been numerous studies demonstrating close bidirectional communication of neurons and glia at structural and functional levels.

Glutamatergic Transmission: A Matter of Three

Neural Plasticity, 2015

Glutamatergic transmission in the vertebrate brain requires the involvement of glia cells, in a continuous molecular dialogue. Glial glutamate receptors and transporters are key molecules that sense synaptic activity and by these means modify their physiology in the short and long term. Posttranslational modifications that regulate protein-protein interactions and modulate transmitter removal are triggered in glial cells by neuronal released glutamate. Moreover, glutamate signaling cascades in these cells are linked to transcriptional and translational control and are critically involved in the control of theso-calledglutamate/glutamine shuttle and by these means in glutamatergic neurotransmission. In this contribution, we summarize our current understanding of the biochemical consequences of glutamate synaptic activity in their surrounding partners and dissect the molecular mechanisms that allow neurons to take control of glia physiology to ensure proper glutamate-mediated neuronal...

Coupling of glutamate and glucose uptake in cultured Bergmann glial cells

Neurochemistry International, 2016

Glutamate, the main excitatory neurotransmitter in the vertebrate brain, exerts its actions through specific membrane receptors present in neurons and glial cells. Over-stimulation of glutamate receptors results in neuronal death, phenomena known as excitotoxicity. A family of sodiumdependent, glutamate uptake transporters mainly expressed in glial cells, removes the amino acid from the synaptic cleft preventing neuronal death. The sustained sodium influx associated to glutamate removal in glial cells, activates the sodium/potassium ATPase restoring the ionic balance, additionally, glutamate entrance activates glutamine synthetase, both events are energy demanding, therefore glia cells increase their ATP expenditure favouring glucose uptake, and triggering several signal transduction pathways linked to proper neuronal glutamate availability, via the glutamate/glutamine shuttle. To further characterize these complex transporters interactions, we used the well-established model system of cultured chick cerebellum Bergmann glia cells. A time and dose-dependent increase in the activity, plasma membrane localization and protein levels of glucose transporters was detected upon D-aspartate exposure. Interestingly, this increase is the result of a protein kinase C-dependent signaling cascade. Furthermore, a glutamate-dependent glucose and glutamate transporters co-immunoprecipitation was detected. These results favour the notion that glial cells are involved in glutamatergic neuronal physiology.

Structural requirements for the inhibition for L-glutamate uptake by glia and nerve endings

Brain Research, 1975

There is good evidence that L-glutamate may be an important excitatory transmitter at many sites in the CNSa and it has been suggested that, in common with other amino acid neurotransmitter candidates, its synaptic actions may be terminated by reuptake into a specific transmitter pool within nerve terminals 22. Although isolated nerve ending fractions will accumulate glutamate by a high-affinity transport process 15, other biochemical evidencel,4,~7, 2a suggests that uptake into glial cells may be of greater significance in terminating transmitter action and indeed glial cells have recently been found to accumulate glutamate by a high-affinity system 1°,~.

News on glutamate receptors in glial cells

Trends in neurosciences, 1996

Glutamate (Glu) receptors convey most of the excitatory synaptic transmission in the mammalian CNS. Distinct Glu-receptor genes and different subtypes of glutamate-activated channels are expressed ubiquitously throughout the developing and mature brain in the two major macroglial cell types, astrocytes and oligodendrocytes. These glial receptors are found in acutely isolated cells and in brain slices, and are therefore functional in vivo. Glutamate receptors in glial cells are activated during neuronal activity, and their activation modulates gene expression in astrocytes and oligodendrocytes. The proliferation and differentiation of glial precursor cells are also regulated by activation of Glu receptors, suggesting that the excitatory transmitter might be one of the environmental signals that regulate glial-cell development.

Regulation of high-affinity glutamate uptake activity in Bergmann glia cells by glutamate

Brain Research, 2000

The effect of glutamate receptor activation on the high-affinity sodium-dependent glutamate transport expressed in chick Bergmann glia 3 cells was examined. Pre-exposure to glutamate produced a time-and dose-dependent decrease in H-labeled D-aspartate uptake. This effect could not be reproduced by selective glutamate receptor agonists. Furthermore, it was insensitive to both ionotropic and metabotropic glutamate receptor antagonists. Replacement of extracellular sodium ions with choline in the preincubation media, abolished the reduction of the uptake. When the cells were pre-exposed to competitive transportable inhibitors of the transporter, such as D-aspartate, DL-threo-hydroxyaspartate (DL-THA), and aspartate-b-hydroxamate (ABH), the glutamate effect was mimicked. From saturation experiments, it was found that the reduction on the uptake, after glutamate treatment, is related to an increase in K . Interestingly, the m 21 effect is blocked by staurosporine, a Ca / diacylglycerol-dependent protein kinase (PKC) inhibitor. The present findings suggest that glutamate regulates its transport in a non-receptor fashion, a phenomena that is most probably linked to changes induced by the translocation process of the substrate through the transporter.