Functional expression of two system A glutamine transporter isoforms in rat auditory brainstem neurons

Blot, Antonin; Billups, Daniela; Bjørkmo, Mona; Quazi, Abrar Z.; Uwechue, Nneka M.; Chaudhry, Farrukh A.; Billups, Brian

doi:10.1016/j.neuroscience.2009.09.015

Cited by 24 publications

(19 citation statements)

References 105 publications

(76 reference statements)

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“…Subsequently, such glutamine release is sensed by MNTB principal neurons which express system A transporters consistent with an intact glutamate/GABA-glutamine cycle (63, 64). Similarly, studies on cultured Bergmann glia cells show that activation of glutamate transporters by d -aspartate results in release of glutamine (65).…”

Section: What Is the Functional Significance Of Sn1 Regulation For Thmentioning

confidence: 99%

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Nissen‐Meyer¹,

Chaudhry²

2013

Front. Endocrinol.

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The system N transporter SN1 (also known as SNAT3) is enriched on perisynaptic astroglial cell membranes. SN1 mediates electroneutral and bidirectional glutamine transport, and regulates the intracellular as well as the extracellular concentrations of glutamine. We hypothesize that SN1 participates in the glutamate/γ-aminobutyric acid (GABA)-glutamine cycle and regulates the amount of glutamine supplied to the neurons for replenishment of the neurotransmitter pools of glutamate and GABA. We also hypothesize that its activity on the plasma membrane is regulated by protein kinase C (PKC)-mediated phosphorylation and that SN1 activity has an impact on synaptic plasticity. This review discusses reports on the regulation of SN1 by PKC and presents a consolidated model for regulation and degradation of SN1 and the subsequent functional implications. As SN1 function is likely also regulated by PKC-mediated phosphorylation in peripheral organs, the same mechanisms may, thus, have impact on e.g., pH regulation in the kidney, urea formation in the liver, and insulin secretion in the pancreas.

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Section: What Is the Functional Significance Of Sn1 Regulation For Thmentioning

confidence: 99%

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Nissen‐Meyer¹,

Chaudhry²

2013

Front. Endocrinol.

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“…1C; n = 10; P < 0.001). These results show that glutamine induces a membrane current in MNTB neurones, which is mediated by the system A glutamine transporters (Blot et al 2009). Any possible role of high-affinity glutamate transporters (EAATs) in generating this postsynaptic current was excluded by showing a lack of effect of the non-transportable EAAT inhibitor TBOA (200 μM) on the glutamine-evoked current (Fig.…”

Section: Mntb Cells Can Act As Glutamine Sensorsmentioning

confidence: 84%

“…1; n = 10; P < 0.001). These results show that glutamine induces a membrane current in MNTB neurones, which is mediated by the system A glutamine transporters (Blot et al . 2009).…”

Section: Resultsmentioning

confidence: 99%

Activation of glutamate transport evokes rapid glutamine release from perisynaptic astrocytes

Uwechue

Marx

Chevy³

et al. 2012

The Journal of Physiology

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Key points• Following release of glutamate from excitatory synapses, excitatory amino acid transporters (EAATs) sequester this glutamate into neighbouring astrocytes.• The signalling effects on the astrocyte and the mechanisms by which this glutamate is recycled back to the synapse are currently unclear.• In this study we use electrophysiological recording from neurones and astrocytes to show that a surge of the neurotransmitter glutamate, as usually occurs during neuronal activity, activates astrocytes and causes them to rapidly release the amino acid glutamine.• This glutamine mediates a fast signal back to the neurones, where it is sequestered and is available for the biosynthesis of further neurotransmitters.• Our data demonstrate a novel feedback mechanism by which astrocytes can potentially modulate neuronal function, and pave the way for development of new therapeutic approaches to treat neurological disorders.Abstract Stimulation of astrocytes by neuronal activity and the subsequent release of neuromodulators is thought to be an important regulator of synaptic communication. In this study we show that astrocytes juxtaposed to the glutamatergic calyx of Held synapse in the rat medial nucleus of the trapezoid body (MNTB) are stimulated by the activation of glutamate transporters and consequently release glutamine on a very rapid timescale. MNTB principal neurones express electrogenic system A glutamine transporters, and were exploited as glutamine sensors in this study. By simultaneous whole-cell voltage clamping astrocytes and neighbouring MNTB neurones in brainstem slices, we show that application of the excitatory amino acid transporter (EAAT) substrate D-aspartate stimulates astrocytes to rapidly release glutamine, which is detected by nearby MNTB neurones. This release is significantly reduced by the toxins L-methionine sulfoximine and fluoroacetate, which reduce glutamine concentrations specifically in glial cells. Similarly, glutamine release was also inhibited by localised inactivation of EAATs in individual astrocytes, using internal DL-threo-β-benzyloxyaspartic acid (TBOA) or dissipating the driving force by modifying the patch-pipette solution. These results demonstrate that astrocytes adjacent to glutamatergic synapses can release glutamine in a temporally precise, controlled manner in response to glial glutamate transporter activation. Since glutamine can be used by neurones as a precursor for glutamate and GABA synthesis, this represents a potential feedback mechanism by which astrocytes can respond to synaptic activation and react in a way that sustains or enhances further communication. This would therefore represent an additional manifestation of the tripartite relationship between synapses and astrocytes.C 2012 The Authors.

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“…Uptake of Na + in astrocytes during re-accumulation of excess extracellular K + from the extracellular space after neuronal excitation (Xu et al, 2013) might therefore increase glutamine release. Extracellular glutamine is taken up into neurons by SAT1,2 (Kanamori and Ross, 2006; Blot et al, 2009; Jenstad et al, 2009). This topic is discussed in detail in the paper by Chaudhry et al in this Research Topic.…”

Section: The Glucose-to-glutamate Pathwaymentioning

confidence: 99%

The Glutamate–Glutamine (GABA) Cycle: Importance of Late Postnatal Development and Potential Reciprocal Interactions between Biosynthesis and Degradation

Hertz¹

2013

Front. Endocrinol.

191

175

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The gold standard for studies of glutamate–glutamine (GABA) cycling and its connections to brain biosynthesis from glucose of glutamate and GABA and their subsequent metabolism are the elegant in vivo studies by 13C magnetic resonance spectroscopy (NMR), showing the large fluxes in the cycle. However, simpler experiments in intact brain tissue (e.g., immunohistochemistry), brain slices, cultured brain cells, and mitochondria have also made important contributions to the understanding of details, mechanisms, and functional consequences of glutamate/GABA biosynthesis and degradation. The purpose of this review is to attempt to integrate evidence from different sources regarding (i) the enzyme(s) responsible for the initial conversion of α-ketoglutarate to glutamate; (ii) the possibility that especially glutamate oxidation is essentially confined to astrocytes; and (iii) the ontogenetically very late onset and maturation of glutamine–glutamate (GABA) cycle function. Pathway models based on the functional importance of aspartate for glutamate synthesis suggest the possibility of interacting pathways for biosynthesis and degradation of glutamate and GABA and the use of transamination as the default mechanism for initiation of glutamate oxidation. The late development and maturation are related to the late cortical gliogenesis and convert brain cortical function from being purely neuronal to becoming neuronal-astrocytic. This conversion is associated with huge increases in energy demand and production, and the character of potentially incurred gains of function are discussed. These may include alterations in learning mechanisms, in mice indicated by lack of pairing of odor learning with aversive stimuli in newborn animals but the development of such an association 10–12 days later. The possibility is suggested that analogous maturational changes may contribute to differences in the way learning is accomplished in the newborn human brain and during later development.

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Functional expression of two system A glutamine transporter isoforms in rat auditory brainstem neurons

Cited by 24 publications

References 105 publications

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Activation of glutamate transport evokes rapid glutamine release from perisynaptic astrocytes

The Glutamate–Glutamine (GABA) Cycle: Importance of Late Postnatal Development and Potential Reciprocal Interactions between Biosynthesis and Degradation

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