Arne Schousboe

..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...

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..It is argued that glycolytically derived energy in the form of ATP may be of particular functional importance in this context...

..Neurotransmitter release was affected by the presence of d-lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment...

..The higher metabolism of isoleucine in muscle could, however, contribute to ammonia fixation and thus likely be of value in the treatment of hepatic encephalopathy...

..In this manuscript, a cascade of events for the preferential neuronal utilization of glucose during neurotransmission is suggested and discussed in relation to our current understanding of neuronal energy metabolism...

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

..In addition, they suggest that the combined inhibition of GAT1 and BGT-1 may afford some advantage over inhibiting either transporter alone...

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

..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...

..Similarly, much larger variation in the distances between transmembrane linker residues in the two protomers comprising the dimer is observed in iGluR5 as compared with iGluR2...

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..Glucose metabolism through the TCA cycle was more decreased than glycolytic activity. Furthermore, reduced glutamate-glutamine cycling was also observed in the obese and type 2 diabetic states...

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

..Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABA(A) receptors...

..It is concluded that this co-culture system serves as a reliable model in which functional and pharmacological aspects of GABA biosynthesis can be investigated...

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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...

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

..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...

..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...

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

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..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...

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

..Based on the experimental findings, DAB can be used to evaluate glycogen shunt activity and its functional importance in intact brain tissue and cells at a concentration of 300-1000 muM and a pre-incubation period of 1 h...

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

..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...

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

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..An overview of the development and characterisation of EF1502 is presented here...

..This provides flexibility with regard to preparation and use of these cultures for a variety of purposes...

..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...

..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...

..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...

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..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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..These models should be an important tool for developing specific drugs that, through selective interaction with transporters, could improve the treatment of serious neurological and psychiatric disorders...

..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...

..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...

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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...

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

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

..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...

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

..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...

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

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

..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...

..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...

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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...

..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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..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...

..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...

..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...

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

..Future analyses of the roles of Gln in both normal and abnormal cerebral metabolism and function will have to account for its newly recognized direct involvement in the regulation of gene transcription and/or translation...

..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...

..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...