Nicergoline Enhances Glutamate Uptake via Glutamate Transporters in Rat Cortical Synaptosomes

In the physiological condition, glutamate acts as an excitatory neurotransmitter in the retina. However, excessive glutamate can be toxic to retinal neurons by overstimulation of the glutamate receptors. Glutamate excess is primarily attributed to perturbation in the homeostasis of the glutamate metabolism. Major pathway of glutamate metabolism consists of glutamate uptake by glutamate transporters followed by enzymatic conversion of glutamate to nontoxic glutamine by glutamine synthetase. Glutamate metabolism requires energy supply, and the energy loss inhibits the functions of both glutamate transporters and glutamine synthetase. In this review, we describe the present knowledge concerning the retinal glutamate metabolism under the physiological and pathological conditions.

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Glutamate Transporters/Na+, K+-ATPase Involving in the Neuroprotective Effect as a Potential Regulatory Target of Glutamate Uptake

Molecular Neurobiology ◽

10.1007/s12035-014-9071-4 ◽

2015 ◽

Vol 53 (2) ◽

pp. 1124-1131 ◽

Cited By ~ 6

Author(s):

Li-Nan Zhang ◽

Yong-Jun Sun ◽

Li-Xue Wang ◽

Zi-Bin Gao

Keyword(s):

Glutamate Uptake ◽

Neuroprotective Effect ◽

Glutamate Transporters

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Bidirectional Neuron–Glia Interactions Triggered by Deficiency of Glutamate Uptake at Spinal Sensory Synapses

Journal of Neurophysiology ◽

10.1152/jn.00282.2010 ◽

2010 ◽

Vol 104 (2) ◽

pp. 713-725 ◽

Cited By ~ 19

Author(s):

Hui Nie ◽

Haijun Zhang ◽

Han-Rong Weng

Keyword(s):

Dorsal Horn ◽

Glial Cells ◽

Synaptic Input ◽

Spinal Dorsal Horn ◽

Glutamate Uptake ◽

Glutamate Transporters ◽

Spinothalamic Tract ◽

Dorsal Horn Neurons ◽

Spinal Dorsal

Bidirectional interactions between neurons and glial cells are crucial to the genesis of pathological pain. The mechanisms regulating these interactions and the role of this process in relaying synaptic input in the spinal dorsal horn remain to be established. We studied the role of glutamate transporters in the regulation of such interactions. On pharmacological blockade of glutamate transporters, slow inward currents (SICs) appeared spontaneously and/or were evoked by peripheral synaptic input in the spinal superficial dorsal horn neurons, including the spinothalamic tract neurons. We showed that the SICs were induced by the release of glutamate from glial cells. On inhibition of glutamate uptake, the stimulation-induced, synaptically released glutamate activated glial cells and caused glial cells to release glutamate. Glial-derived glutamate acted on extrasynaptic N-methyl-d-aspartate (NMDA) receptors mainly composed of NR2B receptors and generated SICs, which led to depolarization and action potential generation in superficial spinal dorsal horn neurons. Thus glutamate transporters regulate glutamatergic neuron–glia interactions at spinal sensory synapses. When glutamate uptake is impaired, glial cells function like excitatory interneurons—they are activated by peripheral synaptic input and release glutamate to activate postsynaptic neurons in spinal pain pathways.

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Effects of inhibiting glutamine synthetase and blocking glutamate uptake on b-wave generation in the isolated rat retina

Visual Neuroscience ◽

10.1017/s095252389916214x ◽

1999 ◽

Vol 16 (2) ◽

pp. 345-353 ◽

Cited By ~ 33

Author(s):

BARRY S. WINKLER ◽

NATALIA KAPOUSTA-BRUNEAU ◽

MATTHEW J. ARNOLD ◽

DANIEL G. GREEN

Keyword(s):

Amino Acids ◽

Glutamine Synthetase ◽

Glutamate Uptake ◽

Müller Cells ◽

Glutamate Transporters ◽

Methionine Sulfoximine ◽

Muller Cells ◽

Rat Retina ◽

Subsequent Conversion ◽

Isolated Rat

The purpose of the present experiments was to evaluate the contribution of the glutamate-glutamine cycle in retinal glial (Müller) cells to photoreceptor cell synaptic transmission. Dark-adapted isolated rat retinas were superfused with oxygenated bicarbonate-buffered media. Recordings were made of the b-wave of the electroretinogram as a measure of light-induced photoreceptor to ON-bipolar neuron transmission. L-methionine sulfoximine (1–10 mM) was added to superfusion media to inhibit glutamine synthetase, a Müller cell specific enzyme, by more than 99% within 5–10 min, thereby disrupting the conversion of glutamate to glutamine in the Müller cells. Threo-hydroxyaspartic acid and D-aspartate were used to block glutamate transporters. The amplitude of the b-wave was well maintained for 1–2 h provided 0.25 mM glutamate or 0.25 mM glutamine was included in the media. Without exogenous glutamate or glutamine the amplitude of the b-wave declined by about 70% within 1 h. Inhibition of glutamate transporters led to a rapid (2–5 min) reversible loss of the b-wave in the presence and absence of the amino acids. In contrast, inhibition of glutamine synthetase did not alter significantly either the amplitude of the b-wave in the presence of glutamate or glutamine or the rate of decline of the b-wave found in the absence of these amino acids. Excellent recovery of the b-wave was found when 0.25 mM glutamate was resupplied to L-methionine sulfoximine–treated retinas. The results suggest that in the isolated rat retina uptake of released glutamate into photoreceptors plays a more important role in transmitter recycling than does uptake of glutamate into Müller cells and its subsequent conversion to glutamine.

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Acute Liver Toxicity Modifies Protein Expression of Glutamate Transporters in Liver and Cerebellar Tissue

Frontiers in Neuroscience ◽

10.3389/fnins.2020.613225 ◽

2021 ◽

Vol 14 ◽

Author(s):

Catya Jiménez-Torres ◽

Hoda El-Kehdy ◽

Luisa C. Hernández-Kelly ◽

Etienne Sokal ◽

Arturo Ortega ◽

...

Keyword(s):

Glutamine Synthetase ◽

Liver Toxicity ◽

Excitatory Amino Acid ◽

Glutamate Uptake ◽

Wide Spectrum ◽

Glutamate Transporters ◽

Dependent Manner ◽

Present Contribution ◽

Differential Expression Pattern ◽

The Brain

Glutamate is the main excitatory amino acid acting at the level of pre and postsynaptic neurons, as well as in glial cells. It is involved in the coordinated modulation of energy metabolism, glutamine synthesis, and ammonia detoxification. The relationship between the functional status of liver and brain has been known for many years. The most widely recognized aspect of this relation is the brain dysfunction caused by acute liver injury that manifests a wide spectrum of neurologic and psychiatric abnormalities. Inflammation, circulating neurotoxins, and impaired neurotransmission have been reported in this pathophysiology. In the present contribution, we report the effect of a hepatotoxic compound like CCl4 on the expression of key proteins involved in glutamate uptake and metabolism as glutamate transporters and glutamine synthetase in mice liver, brain, and cerebellum. Our findings highlight a differential expression pattern of glutamate transporters in cerebellum. A significant Purkinje cells loss, in parallel to an up-regulation of glutamine synthetase, and astrogliosis in the brain have also been noticed. In the intoxicated liver, glutamate transporter 1 expression is up-regulated, in contrast to glutamine synthetase which is reduced in a time-dependent manner. Taken together our results demonstrate that the exposure to an acute CCl4 insult, leads to the disruption of glutamate transporters expression in the liver-brain axis and therefore a severe alteration in glutamate-mediated neurotransmission might be present in the central nervous system.

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pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

Journal of Neurophysiology ◽

10.1152/jn.01074.2012 ◽

2013 ◽

Vol 110 (2) ◽

pp. 368-377 ◽

Cited By ~ 18

Author(s):

Rafiq Huda ◽

Donald R. McCrimmon ◽

Marco Martina

Keyword(s):

Synaptic Transmission ◽

Glutamate Uptake ◽

Glutamate Release ◽

Glutamate Transporters ◽

Functional Expression ◽

Repetitive Stimulation ◽

Solitary Tract ◽

Extracellular Acidification ◽

Sensory Afferents ◽

Selective Membrane

The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl- threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents.

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