Kinetics of 2-Oxoglutarate Uptake by Synaptosomes from Bovine and Rat Retina and Cerebral Cortex and Regulation by Glutamate and Glutamine

Lehmann, John; Kapkov, Denis; Shank, Richard P.

doi:10.1159/000111352

Cited by 6 publications

(8 citation statements)

References 17 publications

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“…The saturation kinetics of [ 14 C]succinate and [ 14 C]citrate uptake by rat astrocytes (K t 28.4 and 1550 lM respectively) determined in the present study are in good agreement with K t values of 2-142 lM (succinate) and 220 lM (citrate), and a K i value of 2.1 mM of citrate for succinate transport, in rodent NaC3 (Chen et al 1998;Kekuda et al 1999;Pajor et al 2001). Pajor et al (2001) have cloned NaC3 from mouse brain, and have speculated that NaC3 might correspond to the NaDC previously identified in glutamatergic synaptosomes (Lehmann et al 1993). However, as shown in Table 3 and our previous reports (Inoue et al 2002b(Inoue et al , 2004, cis-inhibition experiments have revealed that NaC2 in neurons can also accept dicarboxylates such as malate, succinate and fumarate with relatively high affinity, as can NaC3 in astrocytes.…”

Section: Discussionsupporting

confidence: 89%

“…Pajor et al . (2001) have cloned NaC3 from mouse brain, and have speculated that NaC3 might correspond to the NaDC previously identified in glutamatergic synaptosomes (Lehmann et al . 1993).…”

Section: Discussionmentioning

confidence: 91%

“…These TCA cycle intermediates are taken up by a Na + ‐coupled transporter on the plasma membrane. Previous studies have identified a high‐affinity Na + ‐coupled transporter for TCA cycle intermediates in synaptosomes prepared from cerebral cortex (Shank and Campbell 1981, 1982; Lehmann et al . 1993).…”

mentioning

confidence: 99%

“…These TCA cycle intermediates are taken up by a Na + -coupled transporter on the plasma membrane. Previous studies have identified a high-affinity Na + -coupled transporter for TCA cycle intermediates in synaptosomes prepared from cerebral cortex Campbell 1981, 1982;Lehmann et al 1993). In addition, a Na + -coupled dicarboxylate transport system with similar functional features has been characterized in primary cultures of glutamatergic neurons and astrocytes (Hertz and Schousboe 1992;Peng et al 1991).…”

mentioning

confidence: 99%

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Functional and molecular identification of sodium‐coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons

Yodoya¹,

Wada²,

Shimada³

et al. 2006

Journal of Neurochemistry

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Na + -coupled carboxylate transporters (NaCs) mediate the uptake of tricarboxylic acid cycle intermediates in mammalian tissues. Of these transporters, NaC3 (formerly known as Na + -coupled dicarboxylate transporter 3, NaDC3/SDCT2) and NaC2 (formerly known as Na + -coupled citrate transporter, NaCT) have been shown to be expressed in brain. There is, however, little information available on the precise distribution and function of both transporters in the CNS. In the present study, we investigated the functional characteristics of Na uptake by unlabeled succinate, N-acetyl-L-aspartate and citrate was 15.9, 155 and 764 lM respectively. In primary cultures of neurons, uptake of citrate was also Na + dependent and saturable with a K t value of 16.2 lM, which was different from that observed in astrocytes, suggesting that different Na + -dependent citrate transport systems are expressed in neurons and astrocytes. RT-PCR and immunocytochemistry revealed that NaC3 and NaC2 are expressed in cerebrocortical astrocytes and neurons respectively. These results are in good agreement with our previous reports on the brain distribution pattern of NaC2 and NaC3 mRNA using in situ hybridization. This is the first report of the differential expression of different NaCs in astrocytes and neurons. These transporters might play important roles in the trafficking of tricarboxylic acid cycle intermediates and related metabolites between glia and neurons.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Functional and molecular identification of sodium‐coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons

Yodoya¹,

Wada²,

Shimada³

et al. 2006

Journal of Neurochemistry

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“…However, more substantive explanations may also pertain, including the expression of other variant forms of GLT1 not yet recognized, or other transporters, such as EAAC1 (He et al, 2000), post-translational modification, or interacting proteins interfering with antibody binding. In addition, some axon terminals may use alternate pathways to resupply excitatory terminals with glutamate (Fonnum, 1984;Shank et al, 1989;Lehmann et al, 1993;Sonnewald et al, 1993;Westergaard et al, 1995;Hertz et al, 1999;Hassel and Brathe, 2000a,b).…”

Section: Glt1 Is Expressed In a Subpopulation Of Axon Terminalsmentioning

confidence: 99%

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

Chen¹,

Mahadomrongkul²,

Berger³

et al. 2004

J. Neurosci.

248

250

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GLT1 is the major glutamate transporter of the brain and has been thought to be expressed exclusively in astrocytes. Although excitatory axon terminals take up glutamate, the transporter responsible has not been identified. GLT1 is expressed in at least two forms varying in the C termini, GLT1a and GLT1b. GLT1 mRNA has been demonstrated in neurons, without associated protein. Recently, evidence has been presented, using specific C terminus-directed antibodies, that GLT1b protein is expressed in neurons in vivo. These data suggested that the GLT1 mRNA detected in neurons encodes GLT1b and also that GLT1b might be the elusive presynaptic transporter. To test these hypotheses, we used variant-specific probes directed to the 3Ј-untranslated regions for GLT1a and GLT1b to perform in situ hybridization in the hippocampus. Contrary to expectation, GLT1a mRNA was the more abundant form. To investigate further the expression of GLT1 in neurons in the hippocampus, antibodies raised against the C terminus of GLT1a and against the N terminus of GLT1, found to be specific by testing in GLT1 knock-out mice, were used for light microscopic and EM-ICC. GLT1a protein was detected in neurons, in 14 -29% of axons in the hippocampus, depending on the region. Many of the labeled axons formed axo-spinous, asymmetric, and, thus, excitatory synapses. Labeling also occurred in some spines and dendrites. The antibody against the N terminus of GLT1 also produced labeling of neuronal processes. Thus, the originally cloned form of GLT1, GLT1a, is expressed as protein in neurons in the mature hippocampus and may contribute significantly to glutamate uptake into excitatory terminals.

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Astrocytes: Glutamate producers for neurons

et al. 1999

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In order for the brain to use the common amino acid glutamate as a neurotransmitter, it has been necessary to introduce a series of innovations that greatly restrict the availability of glutamate, so that it cannot degrade the signal-to-noise ratio of glutamatergic neurons. The most far-reaching innovations have been: i) to exclude the brain from access to glutamate in the systemic circulation by the blood-brain barrier, thereby making the brain autonomous in the production and disposal of glutamate; ii) to surround glutamatergic synapses with glial cells and endow these cells with much more powerful glutamate uptake carriers than the neurons themselves, so that most released transmitter glutamate is rapidly inactivated by uptake in glial cells; iii) to restrict to glial cells a key enzyme (glutamine synthetase) that is involved in the return of accumulated glutamate to neurons by amidation to glutamine, which has no transmitter activity, and can be safely released to the extracellular space, returned to neurons and deaminated to glutamate; iv) to restrict to glial cells two key enzymes (pyruvate carboxylase and cytosolic malic enzyme) that are involved in, respectively, de novo synthesis (from glucose) of the carbon skeleton of glutamate, and the return of the carbon skeleton of excess glutamate to the metabolic pathway for glucose oxidation. As a consequence of these innovations, neurons constantly require new carbon skeletons from glial to sustain their TCA cycle. When these supplies are withdrawn, neurons are unable to generate amino acid transmitters and their rate of oxidative metabolism is impaired. Given the commensalism that exists between neurons and glia, it may be fruitful to view brain function not just as a series of interactions between neurons, but also as a series of interactions between neurons and their collaborating glial cells.

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Kinetics of 2-Oxoglutarate Uptake by Synaptosomes from Bovine and Rat Retina and Cerebral Cortex and Regulation by Glutamate and Glutamine

Cited by 6 publications

References 17 publications

Functional and molecular identification of sodium‐coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons

Functional and molecular identification of sodium‐coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons

The Glutamate Transporter GLT1a Is Expressed in Excitatory Axon Terminals of Mature Hippocampal Neurons

Astrocytes: Glutamate producers for neurons

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