A Schousboe

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..As such, selective targeting and modulation of GABA transporter subtypes and cell-specific GABA uptake and metabolism is of therapeutical interest in GABA-related CNS disorders, including epilepsy...

..Therefore drugs exhibiting selective agonist or antagonist action on subclasses of GABA(A) and GABA(B) may be of potential use as regulators of glutamatergic excitatory activity...

..It has moreover been reported to act as an anticonvulsant in animal models of epilepsy. This may underline the functional importance of astrocytic GABA uptake in relation to seizure activity...

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..The compartments differ with regard to utilization of lactate and glucose, synthetic pathways for TCA cycle intermediates and amino acids, particularly citrate and glutamine, as well as the contents of different metabolites...

..Both isoforms were found in the cultured cerebral cortical neurons, as shown by Western blotting employing an antibody recognizing GAD(65) as well as GAD(67)...

..The formation of NAPE and NAE may represent a cytoprotective response in relation to various forms of neurotoxicity...

..This opens for a number of therapeutic strategies by which the efficacy of excitatory and inhibitory neurotransmission may be manipulated...

..At pHo 8.2, the alkalinization was significantly increased, while at pHo 6.2, the initial acidification was followed by further acidification in about 50% of the cells, and by no further change in the remaining cells...

..It may be suggested that these enzymes form a complex with the transporters and the Na(+) /K(+) -ATPase, the latter providing the sodium gradient required for the transport process...

..Altogether, the results reveal a highly complex interaction between glycogenolysis and glycolysis, with the glycogen shunt playing a significant role in astrocytic energy metabolism...

..Based on the present results it may be safely concluded that neuronal pyruvate carboxylation is unlikely to be of quantitative significance...

..It is suggested that DL-TBOA may be used to selectively inhibit depolarization coupled glutamate release mediated by reversal of the carriers...

..The components of direct AMPA-R-mediated toxicity are proposed to be 1) toxicity mediated by GluR2(R)-lacking AMPA-R and 2) toxicity mediated by low-Ca(2+)-permeability AMPA-R containing GluR2(R)...

..025) in the membrane expression of GLAST. In case of GLT-1, culture in the presence of 30 microM topiramate for 1 and 10 days led to alterations in the total, cytoplamic and membrane expression of the oligomeric form of the transporter...

..e., alpha1, gamma2, alpha1beta2, beta2gamma2), where higher molecular weight forms were strongly represented. These findings show that alpha1 and gamma2 prefer specific protein forms when expressed together...

..The activity-dependent trafficking of this transporter which also exhibits properties of a glutamate-gated chloride channel may play functional roles not only in neuronal excitability, but in glioma cell biology as well...

..In particular, it is suggested that the acidity of the terminal group plays a major role in determining the degree of receptor activation in the steady state...

..Moreover, desensitization was observed for the (alpha1/gamma2)beta2gamma2 receptor with respect to the direct activation by pentobarbital. This suggests differences in the mechanism of channel activation for pentobarbital and GABA...

..These aspects are discussed in relation to the different functional roles of GABA and its prominent involvement in epileptogenic activity...

..The anandamide precursor is up-regulated to the same extent as other NAPEs upon neuronal injury...

..It is concluded that the metabolites 3-OH-GA, GA, and TG are only weak neurotoxins and that the neurodegenerative cascade destroying the striatum in patients with GA1 involves mainly mechanisms other than excitoxicity...

..A summary of these and other issues are discussed in this brief review...

..It is hypothesized that extrasynaptic actions of GABA may be involved in this phenomenon...

..Collectively, these findings support a functional role for mGAT2 in the control of neuronal excitability and suggest a possible utility for mGAT2-selective inhibitors in the treatment of epilepsy...

..No direct coupling of the two shuttles was observed, however, and only the glutamate-glutamine cycle seemed activity dependent...

..By providing an ordered membrane microenvironment, lipid rafts may contribute to the clustering of the GABA(A) receptor and the Na(+), K(+)-ATPase at distinct functional locations on the cell surface...

..Additionally, pharmacological and therapeutic aspects of this will be discussed...

..Taken together, these results indicate that astroglial GAT2 expression and function may be regulated by hyperosmolarity in cultured mouse astrocytes, suggesting a role of GAT2 in osmoregulation in neural cells...

..In conclusion, the present study shows that GABA synthesis is taking place via GAD in a subpopulation of the cerebellar neurons, throughout the culture period...

..Moreover, it should be noted that the amino acid neurotransmitters can be used as metabolic substrates. This requires pyruvate recycling, a process that is discussed as well...

..This has led to development of clinically efficatious antiepileptic drugs. This paper shall review recent progress in targeting these pharmacological entities...

..These results show that metabolism of pyruvate, the precursor for lactate, alanine and acetyl-CoA is highly compartmentalized...

..Inhibition of either degradation or clearance of GABA has been successfully applied in the development of antiepileptics such as vigabatrin or tiagabine. So far, no specific strategy has been developed aimed at stimulating Glu transport...

..Furthermore, results obtained with the N-methyl-exo-THPO prodrug demonstrate the feasibility of developing a glial-selective GABA uptake inhibitor with systemic bioavailability...

..5 mM glutamine exogenously supplied is inadequate to sustain this pool...

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..Although this may partly be due to more rapid depletion of glutamate in the co-cultures, this observation at the very least indicates that pyruvate recycling is not up-regulated in the neuronal-astrocytic co-cultures...

..There was, however, an increase in GABA sensitivity (EC(50) = 1.3 microm) compared with the wild type receptor (EC(50) = 6.4 microm) and a loss of desensitization to GABA of the mutant receptor...

..It is suggested that valine in particular might have an important function as an amino acid translocated between neuronal and astrocytic compartments, a function that might be up-regulated during synaptic activity...

..In conclusion, i) neuronal and astrocytic TCA cycle metabolism was not inhibited by ammonium and ii) isoleucine may provide the carbon skeleton for synthesis of glutamate/glutamine in the detoxification of ammonium...

..Hence more sophisticated analytical methods are warranted in order to obtain a definite answer to this important question...

..Collectively the results show that transport of glutamine into the mitochondrial matrix may be a prerequisite for deamidation by PAG...

..01). The present findings suggest that this TM1 glycine residue is critical for the rate at which desensitization occurs and that both GABA and intravenous anesthetics implement an analogous pathway for generating desensitization...

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..Both enantiomers induce full domain closure in iGluR2 but adopt different conformations when binding to the receptor, which may explain the similar enantiopharmacology...

..Contemporary theoretical models for functional neuroimaging will be revised in the fourth part, with particular emphasis in their applications, advantages/limitations and future prospects...

..The results show that this preparation of brain tissue with intact cellular networks is well suited to study metabolism and release of neurotransmitter amino acids under conditions mimicking neural activity...

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..The complementary localization patterns observed for two different isoforms of the Ca(v)2.1 subunits provide direct evidence for alternative splicing as a means of generating functional diversity among neuronal calcium channels...

..A main objective of this review is to endorse the view that the glutamate/GABA-glutamine cycle must be seen as a bi-directional transfer of not only carbon units but also nitrogen units...

..These results suggest that (S)-CPW 399 may be used as a pharmacological tool to aid in the investigation of the role of AMPA receptors in excitotoxicity and their molecular mechanisms of desensitisation...

..It is likely that the high glutamate concentration (100 microM) may facilitate heteroexchange of the preloaded [3H]D-aspartate...

..Several biological effects induced by GABA in the developing nervous system are reviewed, with particular emphasis on what is known about calcium-dependent neurotrophic effects induced by GABA and its intracellular mechanisms...

..The results indicate that astrocytes, but not neurons, generate free radicals following glutamine exposure. Glutamine-induced oxidative and/or nitrosative stress may represent a key mechanism in ammonia neurotoxicity...

..Topiramate, at concentrations of 30 and 100 microM, inhibited Ca2+ influx by up to 60%. Modulation of AMPA and KA-evoked Ca2+ influx may contribute to both the antiepileptic and neuroprotective properties of topiramate...

..Therefore it must be concluded that the newly synthesized GABA is redistributed among the majority of the cells in these cultures, i.e. the glutamatergic neurones...

..Further experiments are needed to elucidate these phenomena that underline the impact of extracellular environment on amino acid homeostasis...

..The CAP area declined more rapidly when glycogen metabolism was inhibited by isofagomine, explicitly showing an important physiological role for glycogen metabolism during neural activity...

..38 at GluR2(Q)i, relative to (S)-glutamate. The proximity of bound (S)-4-AHCP to domain D2 prevents full D1-D2 domain closure, which is limited by steric repulsion, especially between Leu704 and the ligand...

..Thus, Cl-HIBO is the most subtype selective agonist reported to date on GluR1/2, and offers a new standard for selectively studying subtypes of AMPA receptors...

..In conclusion, this study underlines the probability that mitochondrial heterogeneity at the single cell level might be extended to involve other metabolic pathways and metabolites...

..Moreover, it was found that lactate originating from glycogen is compartmentalized from that derived from glucose, which lends further support to a compartmentalized metabolism in astrocytes...

..This report evaluates the evidence for each shuttle in brain cells and the drugs that can be used as pharmacological tools to study these shuttles...

..Thus, malfunction of astrocytic glutamate transporters will lead to an excessively high extracellular glutamate concentration which may result in neurodegeneration caused by the excitotoxic action of glutamate...

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..The displacement of (S)-glutamate by all antagonists was shown to be driven by enthalpy...

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..It is likely that metabolism may be far more complex than this and we are only beginning to glimpse some aspects of compartmentation at the cellular level...