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Roles of glutamine in neurotransmission

Published online by Cambridge University Press:  21 October 2011

Jan Albrecht ,
Marta Sidoryk-Węgrzynowicz ,
Magdalena Zielińska  and
Michael Aschner
Jan Albrecht*
Affiliation:
Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Marta Sidoryk-Węgrzynowicz
Affiliation:
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
Magdalena Zielińska
Affiliation:
Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Michael Aschner*
Affiliation:
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
*
Correspondence should be addressed to: Jan Albrecht and Michael Aschner, phone: 4822 6086617 (J.A.)/ + 615 3228024 (M.A.), fax: 4822 6086422 (J.A.)/ + 615 9364080 (M.A.) emails: jalb@cmdik.pan.pl (J.A.)/michael.aschner@vanderbilt.edu (M.A.)
Correspondence should be addressed to: Jan Albrecht and Michael Aschner, phone: 4822 6086617 (J.A.)/ + 615 3228024 (M.A.), fax: 4822 6086422 (J.A.)/ + 615 9364080 (M.A.) emails: jalb@cmdik.pan.pl (J.A.)/michael.aschner@vanderbilt.edu (M.A.)
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Abstract

Glutamine (Gln) is found abundantly in the central nervous system (CNS) where it participates in a variety of metabolic pathways. Its major role in the brain is that of a precursor of the neurotransmitter amino acids: the excitatory amino acids, glutamate (Glu) and aspartate (Asp), and the inhibitory amino acid, γ-amino butyric acid (GABA). The precursor–product relationship between Gln and Glu/GABA in the brain relates to the intercellular compartmentalization of the Gln/Glu(GABA) cycle (GGC). Gln is synthesized from Glu and ammonia in astrocytes, in a reaction catalyzed by Gln synthetase (GS), which, in the CNS, is almost exclusively located in astrocytes (Martinez-Hernandez et al., 1977). Newly synthesized Gln is transferred to neurons and hydrolyzed by phosphate-activated glutaminase (PAG) to give rise to Glu, a portion of which may be decarboxylated to GABA or transaminated to Asp. There is a rich body of evidence which indicates that a significant proportion of the Glu, Asp and GABA derived from Gln feed the synaptic, neurotransmitter pools of the amino acids. Depolarization-induced-, calcium- and PAG activity-dependent releases of Gln-derived Glu, GABA and Asp have been observed in CNS preparations in vitro and in the brain in situ. Immunocytochemical studies in brain slices have documented Gln transfer from astrocytes to neurons as well as the location of Gln-derived Glu, GABA and Asp in the synaptic terminals. Patch-clamp studies in brain slices and astrocyte/neuron co-cultures have provided functional evidence that uninterrupted Gln synthesis in astrocytes and its transport to neurons, as mediated by specific carriers, promotes glutamatergic and GABA-ergic transmission. Gln entry into the neuronal compartment is facilitated by its abundance in the extracellular spaces relative to other amino acids. Gln also appears to affect neurotransmission directly by interacting with the NMDA class of Glu receptors. Transmission may also be modulated by alterations in cell membrane polarity related to the electrogenic nature of Gln transport or to uncoupled ion conductances in the neuronal or glial cell membranes elicited by Gln transporters. In addition, Gln appears to modulate the synthesis of the gaseous messenger, nitric oxide (NO), by controlling the supply to the cells of its precursor, arginine. Disturbances of Gln metabolism and/or transport contribute to changes in Glu-ergic or GABA-ergic transmission associated with different pathological conditions of the brain, which are best recognized in epilepsy, hepatic encephalopathy and manganese encephalopathy.

Keywords

GlnGluGABAastrocytessynaptic endingsneural transmissionneuromodulationbrain pathology
Type
Research Article
Information
Neuron Glia Biology , Volume 6 , Issue 4 , November 2010 , pp. 263 - 276
Copyright
Copyright © Cambridge University Press 2011

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References

REFERENCES

Albrecht, J. (1989) L-glutamate stimulates the efflux of newly taken up glutamine from astroglia but not from synaptosomes of the rat. Neuropharmacology 28, 885–887.CrossRefGoogle Scholar
Albrecht, J. and Jones, E.A. (1999) Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. Journal of the Neurological Sciences 170, 138–146; doi:S0022-510X(99)00169-0 [pii].CrossRefGoogle ScholarPubMed
Albrecht, J. and Norenberg, M.D. (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44, 788–794; doi:10.1002/hep.21357.CrossRefGoogle ScholarPubMed
Albrecht, J., Zielinska, M. and Norenberg, M.D. (2010) Glutamine as a mediator of ammonia neurotoxicity: a critical appraisal. Biochemical Pharmacology 80, 1303–1308; doi:S0006-2952(10)00535-6 [pii], 10.1016/j.bcp.2010.07.024.CrossRefGoogle ScholarPubMed
Alpers, D.H. (2006) Glutamine: do the data support the cause for glutamine supplementation in humans? Gastroenterology 130, S106–S116; doi:S0016-5085(05)02423-6 [pii], 10.1053/j.gastro.2005.11.049.CrossRefGoogle ScholarPubMed
Alvestad, S., Hammer, J., Eyjolfsson, E., Qu, H., Ottersen, O.P. and Sonnewald, U. (2008) Limbic structures show altered glial-neuronal metabolism in the chronic phase of kainate induced epilepsy. Neurochemical Research 33, 257–266; doi:10.1007/s11064-007-9435-5.CrossRefGoogle ScholarPubMed
Anderson, P., Cooney, T. and Erikson, K.M. (2007) Brain manganese accumulation is inversely related to GABA uptake in male and female rats. Toxicological Sciences 95, 188–195.CrossRefGoogle ScholarPubMed
Aschner, M., Gannon, M. and Kimelberg, H.K. (1992) Manganese uptake and efflux in cultured rat astrocytes. Journal of Neurochemistry 58, 730–735.CrossRefGoogle ScholarPubMed
Bacci, A., Sancini, G., Verderio, C., Armano, S., Pravettoni, E., Fesce, R. et al. (2002) Block of glutamate-glutamine cycle between astrocytes and neurons inhibits epileptiform activity in hippocampus. Journal of Neurophysiology 88, 2302–2310; doi:10.1152/jn.00665.2001.CrossRefGoogle ScholarPubMed
Bachelard, H. (1998) Landmarks in the application of I3C-magnetic resonance spectroscopy to studies of neuronal/glial relationships. Developmental Neuroscience 20, 277–288.CrossRefGoogle ScholarPubMed
Bak, L.K., Schousboe, A. and Waagepetersen, H.S. (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. Journal of Neurochemistry 98, 641–653; doi:JNC3913 [pii], 10.1111/j.1471-4159.2006.03913.x.CrossRefGoogle ScholarPubMed
Balkrishna, S., Broër, A., Kingsland, A. and Broër, S. (2010) Rapid downregulation of the rat glutamine transporter SNAT3 by a caveolin-dependent trafficking mechanism in Xenopus laevis oocytes. American Journal of Physiology – Cell Physiology 299, C1047–C1057; doi:ajpcell.00209.2010 [pii], 10.1152/ajpcell.00209.2010.CrossRefGoogle ScholarPubMed
Bhalla, V., Daidie, D., Li, H., Pao, A.C., LaGrange, L.P., Wang, J. et al. (2005) Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4–2 by inducing interaction with 14-3-3. Molecular Endocrinology 19, 3073–3084; doi:me.2005-0193 [pii], 10.1210/me.2005-0193.CrossRefGoogle ScholarPubMed
Bidmon, H.J., Gorg, B., Palomero-Gallagher, N., Schleicher, A., Haussinger, D., Speckmann, E.J. et al. (2008) Glutamine synthetase becomes nitrated and its activity is reduced during repetitive seizure activity in the pentylentetrazole model of epilepsy. Epilepsia 49, 1733–1748; doi:EPI1642 [pii], 10.1111/j.1528-1167.2008.01642.x.CrossRefGoogle ScholarPubMed
Blei, A.T. (2007) Brain edema in acute liver failure: can it be prevented? Can it be treated? Journal of Hepatology 46, 564–569; doi:S0168-8278(07)00052-9 [pii], 10.1016/j.jhep.2007.01.011.CrossRefGoogle ScholarPubMed
Boehmer, C., Laufer, J., Jeyaraj, S., Klaus, F., Lindner, R., Lang, F. et al. (2008) Modulation of the voltage-gated potassium channel Kv1.5 by the SGK1 protein kinase involves inhibition of channel ubiquitination. Cellular Physiology and Biochemistry 22, 591–600; doi:000185543 [pii], 10.1159/000185543.CrossRefGoogle ScholarPubMed
Boehmer, C., Okur, F., Setiawan, I., Broër, S. and Lang, F. (2003) Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB. Biochemical and Biophysical Research Communications 306, 156–162; doi:S0006291X03009215 [pii].CrossRefGoogle ScholarPubMed
Boulland, J.L., Osen, K.K., Levy, L.M., Danbolt, N.C., Edwards, R.H., Storm-Mathisen, J. and Chaudhry, F.A. (2002) Cell-specific expression of the glutamine transporter SN1 suggests differences in dependence on the glutamine cycle. European Journal of Neuroscience 5, 1615–1631.CrossRefGoogle Scholar
Bradford, H.F., Ward, H.K. and Foley, P. (1989) Glutaminase inhibition and the release of neurotransmitter glutamate from synaptosomes. Brain Research 476, 29–34; doi:0006-8993(89)91533-3 [pii].CrossRefGoogle ScholarPubMed
Brasse-Lagnel, C., Lavoinne, A. and Husson, A. (2009) Control of mammalian gene expression by amino acids, especially glutamine. FEBS Journal 276, 1826–1844; doi:EJB6920 [pii], 10.1111/j.1742-4658.2009.06920.x.CrossRefGoogle ScholarPubMed
Brasse-Lagnel, C., Lavoinne, A., Loeber, D., Fairand, A., Bôle-Feysot, C., Deniel, N. and Husson, A. (2003) Glutamine and interleukin-1beta interact at the level of Sp1 and nuclear factor-kappaB to regulate argininosuccinate synthetase gene expression. Federation of European Biochemical Societies Journal 274, 5250–5262.Google Scholar
Broër, A., Deitmer, J.W. and Broër, S. (2004) Astroglial glutamine transport by system N is upregulated by glutamate. Glia 48, 298–310; doi:10.1002/glia.20081.CrossRefGoogle ScholarPubMed
Broër, A., Friedrich, B., Wagner, C.A., Fillon, S., Ganapathy, V., Lang, F. et al. (2001) Association of 4F2hc with light chains LAT1, LAT2 or y + LAT2 requires different domains. Biochemical Journal 355, 725–731.CrossRefGoogle ScholarPubMed
Broër, A., Wagner, C.A., Lang, F. and Broër, S. (2000) The heterodimeric amino acid transporter 4F2hc/y + LAT2 mediates arginine efflux in exchange with glutamine. Biochemical Journal 349, 787–795.CrossRefGoogle ScholarPubMed
Bröer, S. and Brookes, N. (2001) Transfer of glutamine between astrocytes and neurons. Journal of Neurochemistry 77, 705–719.CrossRefGoogle ScholarPubMed
Cavus, I., Kasoff, W.S., Cassaday, M.P., Jacob, R., Gueorguieva, R., Sherwin, R.S. et al. (2005) Extracellular metabolites in the cortex and hippocampus of epileptic patients. Annals of Neurology 57, 226–235; doi:10.1002/ana.20380.CrossRefGoogle ScholarPubMed
Castilho, R.F., Ward, M.W. and Nicholls, D.G. (1999) Oxidative stress, mitochondrial function, and acute glutamate excitotoxicity in cultured cerebellar granule cells. Journal of Neurochemistry 72, 1394–1401.CrossRefGoogle ScholarPubMed
Chaudhry, F.A., Krizaj, D., Larsson, P., Reimer, R.J., Wreden, C., Storm-Mathisen, J. et al. (2001) Coupled and uncoupled proton movement by amino acid transport system N. EMBO Journal 20, 7041–7051; doi:10.1093/emboj/20.24.7041.CrossRefGoogle ScholarPubMed
Chaudhry, F.A., Reimer, R.J. and Edwards, R.H. (2002) The glutamine commute: take the N line and transfer to the A. Journal of Cell Biology 157, 349–355; doi:10.1083/jcb.200201070, jcb.200201070 [pii].CrossRefGoogle Scholar
Conn, H.O. and Bircher, J. (1994) Hepatic Encephalopathies: Syndromes and Therapies. Medi-Ed Press, Bloomington, pp. 1–13.Google Scholar
Conti, F. and Melone, M. (2006) The glutamine commute: lost in the tube? Neurochemistry International 48, 459–464; doi:S0197-0186(06)00038-6 [pii], 10.1016/j.neuint.2005.11.016.CrossRefGoogle ScholarPubMed
Conti, F. and Minelli, A. (1994) Glutamate immunoreactivity in rat cerebral cortex is reversibly abolished by 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of phosphate-activated glutaminase. Journal of Histochemistry and Cytochemistry 42, 717–726.CrossRefGoogle ScholarPubMed
Corless, M., Kiely, A., McClenaghan, N.H., Flatt, P.R. and Newsholme, P. (2006) Glutamine regulates expression of key transcription factor, signal transduction, metabolic gene, and protein expression in a clonal pancreatic beta-cell line. Journal of Endocrinology 190, 719–727; doi:190/3/719 [pii], 10.1677/joe.1.06892.CrossRefGoogle Scholar
Cotzias, G.C. (1958) Manganese in health and disease. Physiological Reviews 38, 503–532.CrossRefGoogle ScholarPubMed
Cruz, F. and Cerdán, S. (1999) Quantitative 13C NMR studies of metabolic compartmentation in the adult mammalian brain. NMR Biomedicine 12, 451–462.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Cubelos, B., Gonzalez-Gonzalez, I.M., Gimenez, C. and Zafra, F. (2005) Amino acid transporter SNAT5 localizes to glial cells in the rat brain. Glia 49, 230–244; doi:10.1002/glia.20106.CrossRefGoogle ScholarPubMed
Debonneville, C., Flores, S.Y., Kamynina, E., Plant, P.J., Tauxe, C., Thomas, M.A. et al. (2001) Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO Journal 20, 7052–7059; doi:10.1093/emboj/20.24.7052.CrossRefGoogle ScholarPubMed
Deitmer, J.W., Broër, A. and Broër, S. (2003) Glutamine efflux from astrocytes is mediated by multiple pathways. Journal of Neurochemistry 87, 127–135; doi:1981 [pii].CrossRefGoogle ScholarPubMed
Dolinska, M., Dybel, A., Hilgier, W., Zielinska, M., Zablocka, B., Buzanska, L. et al. (2001) Glutamine transport in C6 glioma cells: substrate specificity and modulation in a glutamine deprived culture medium. Journal of Neuroscience Research 66, 959–966; doi:10.1002/jnr.10047 [pii].CrossRefGoogle Scholar
During, M.J. and Spencer, D.D. (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341, 1607–1610; doi:0140-6736(93)90754-5 [pii].CrossRefGoogle ScholarPubMed
Dye, J.F., Vause, S., Johnston, T., Clark, P., Firth, J.A., D'Souza, S.W. et al. (2004) Characterization of cationic amino acid transporters and expression of endothelial nitric oxide synthase in human placental microvascular endothelial cells. FASEB Journal 18, 125–127; doi:10.1096/fj.02-0916fje, 02-0916fje [pii].CrossRefGoogle ScholarPubMed
Eid, T., Hammer, J., Runden-Pran, E., Roberg, B., Thomas, M.J., Osen, K. et al. (2007) Increased expression of phosphate-activated glutaminase in hippocampal neurons in human mesial temporal lobe epilepsy. Acta Neuropathologica 113, 137–152; doi:10.1007/s00401-006-0158-5.CrossRefGoogle ScholarPubMed
Eid, T., Thomas, M.J., Spencer, D.D., Runden-Pran, E., Lai, J.C., Malthankar, G.V. et al. (2004) Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363, 28–37; doi:S0140673603151665 [pii].CrossRefGoogle ScholarPubMed
Eloqayli, H., Dahl, C.B., Gotestam, K.G., Unsgard, G. and Sonnewald, U. (2004) Changes of glial-neuronal interaction and metabolism after a subconvulsive dose of pentylenetetrazole. Neurochemistry International 45, 739–745; doi:10.1016/j.neuint.2004.02.002, S0197018604000312 [pii].CrossRefGoogle ScholarPubMed
Erikson, K. and Aschner, M. (2002) Manganese causes differential regulation of glutamate transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes. Neurotoxicology 23, 595–602; doi:S0161-813X(02)00012-8 [pii].CrossRefGoogle ScholarPubMed
Erikson, K.M., Dorman, D.C., Lash, L.H. and Aschner, M. (2008) Duration of airborne-manganese exposure in rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity. Neurotoxicology 29, 377–85.CrossRefGoogle ScholarPubMed
Erikson, K.M., Syversen, T., Aschner, J.L. and Aschner, M. (2005) Interactions between excessive manganese exposures and dietary iron-deficiency in neurodegeneration. Environmental Toxicology and Pharmacology 19, 415–421.CrossRefGoogle ScholarPubMed
Felipo, V. (2006) Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy. World Journal of Gastroenterology 12, 7737–7743.CrossRefGoogle Scholar
Felipo, V. and Butterworth, R.F. (2002) Neurobiology of ammonia. Progress in Neurobiology 67, 259–279; doi:S0301008202000199 [pii].CrossRefGoogle ScholarPubMed
Fitsanakis, V.A., Au, C., Erikson, K.M. and Aschner, M. (2006) The effects of manganese on glutamate, dopamine and gamma-aminobutyric acid regulation. Neurochemistry International 48, 426–433; doi:S0197-0186(06)00033-7 [pii], 10.1016/j.neuint.2005.10.012.CrossRefGoogle ScholarPubMed
Fordahl, S.C., Anderson, J.G., Cooney, P.T., Weaver, T.L., Colyer, C.L. and Erikson, K.M. (2010) Manganese exposure inhibits the clearance of extracellular GABA and influences taurine homeostasis in the striatum of developing rats. Neurotoxicology 31, 639–646; doi:S0161-813X(10)00181-6 [pii], 10.1016/j.neuro.2010.09.002.CrossRefGoogle ScholarPubMed
Fricke, M.N., Jones-Davis, D.M. and Mathews, G.C. (2007) Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission. Journal of Neurochemistry 102, 1895–1904; doi:JNC4649 [pii], 10.1111/j.1471-4159.2007.04649.x.CrossRefGoogle ScholarPubMed
Gallo, V., Ciotti, M.T., Coletti, A., Aloisi, F. and Levi, G. (1982) Selective release of glutamate from cerebellar granule cells differentiating in culture. Proceedings of the National Academy of Sciences of the U.S.A. 79, 7919–7923.CrossRefGoogle ScholarPubMed
Gauchy, C., Kemel, M.L., Glowinski, J. and Besson, M.J. (1980) In vivo release of endogenously synthesized [3H]GABA from the cat substantia nigra and the pallido-entopeduncular nuclei. Brain Research 193, 129–141; doi:0006-8993(80)90950-6 [pii].CrossRefGoogle ScholarPubMed
Gonzalez, M.I., Susarla, B.T. and Robinson, M.B. (2005) Evidence that protein kinase Calpha interacts with and regulates the glial glutamate transporter GLT-1. Journal of Neurochemistry 94, 1180–1188; doi:JNC3330 [pii], 10.1111/j.1471-4159.2005.03330.x.CrossRefGoogle ScholarPubMed
Gruetter, R., Novotny, E.J., Boulware, S.D., Mason, G.F., Rothman, D.L., Shulman, G.I. et al. (1994) Localized 13C NMR spectroscopy in the human brain of amino acid labeling from D-[1-13C]glucose. Journal of Neurochemistry 63, 1377–1385.CrossRefGoogle Scholar
Gruetter, R., Seaquist, E.R., Kim, S. and Ugurbil, K. (1998) Localized in vivo 13C-NMR of glutamate metabolism in the human brain: initial results at 4 tesla. Developmental Neuroscience 20, 380–388; doi:dne20380 [pii].CrossRefGoogle Scholar
Guilarte, T.R., Burton, N.C., Verina, T., Prabhu, V.V., Becker, K.G., Syversen, T. et al. (2008) Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. Journal of Neurochemistry 105, 1948–1959; doi:JNC5295 [pii], 10.1111/j.1471-4159.2008.05295.x.CrossRefGoogle ScholarPubMed
Guillet, B.A., Velly, L.J., Canolle, B., Masmejean, F.M., Nieoullon, A.L. and Pisano, P. (2005) Differential regulation by protein kinases of activity and cell surface expression of glutamate transporters in neuron-enriched cultures. Neurochemistry International 46, 337–346; doi:S0197-0186(04)00184-6 [pii], 10.1016/j.neuint.2004.10.006.CrossRefGoogle ScholarPubMed
Gundersen, V., Chaudhry, F.A., Bjaalie, J.G., Fonnum, F., Ottersen, O.P. and Storm-Mathisen, J. (1998) Synaptic vesicular localization and exocytosis of L-aspartate in excitatory nerve terminals: a quantitative immunogold analysis in rat hippocampus. Journal of Neuroscience 18, 6059–6070.CrossRefGoogle ScholarPubMed
Hagglund, M.G., Sreedharan, S., Nilsson, V.C., Shaik, J.H., Almkvist, I.M., Backlin, S. et al. (2011) Identification of SLC38A7 (SNAT7) protein as a glutamine transporter expressed in neurons. Journal of Biological Chemistry 286, 20500–20511; doi:M110.162404 [pii], 10.1074/jbc.M110.162404.CrossRefGoogle ScholarPubMed
Hall, J.C., Heel, K. and McCauley, R. (1996) Glutamine. British Journal of Surgery 83, 305–312.CrossRefGoogle ScholarPubMed
Hamberger, A., Chiang, G.H., Sandoval, E. and Cotman, C.W. (1979a) Glutamate as a CNS transmitter. II. Regulation of synthesis in the releasable pool. Brain Research 168, 531–541.CrossRefGoogle ScholarPubMed
Hamberger, A. and Nystrom, B. (1984) Extra- and intracellular amino acids in the hippocampus during development of hepatic encephalopathy. Neurochemical Research 9, 1181–1192.CrossRefGoogle ScholarPubMed
Hamberger, A.C., Chiang, G.H., Nylen, E.S., Scheff, S.W. and Cotman, C.W. (1979b) Glutamate as a CNS transmitter. I. Evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate. Brain Research 168, 513–530; doi:0006-8993(79)90306-8 [pii].CrossRefGoogle ScholarPubMed
Hauser, W.A. and Kurland, L.T. (1975) The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 16, 1–66.CrossRefGoogle ScholarPubMed
Haussinger, D. and Schliess, F. (2007) Glutamine metabolism and signaling in the liver. Frontiers in Bioscience 12, 371–391; doi:2070 [pii].CrossRefGoogle ScholarPubMed
Hertz, L., Dringen, R., Schousboe, A. and Robinson, S.R. (1999) Astrocytes: glutamate producers for neurons. Journal of Neuroscience Research 57, 417–428; doi:10.1002/(SICI)1097-4547(19990815)57:4 < 417::AID-JNR1 > 3.0.CO;2-N [pii].3.0.CO;2-N>CrossRefGoogle ScholarPubMed
Hilgier, W., Fresko, I., Klemenska, E., Beresewicz, A., Oja, S.S., Saransaari, P. et al. (2009) Glutamine inhibits ammonia-induced accumulation of cGMP in rat striatum limiting arginine supply for NO synthesis. Neurobiology of Disease 35, 75–81; doi:S0969-9961(09)00081-3 [pii], 10.1016/j.nbd.2009.04.004.CrossRefGoogle ScholarPubMed
Hilgier, W., Wegrzynowicz, M., Maczewski, M., Beresewicz, A., Oja, S.S., Saransaari, P. et al. (2008) Effect of glutamine synthesis inhibition with methionine sulfoximine on the nitric oxide-cyclic GMP pathway in the rat striatum treated acutely with ammonia: a microdialysis study. Neurochemical Research 33, 267–272; doi:10.1007/s11064-007-9455-1.CrossRefGoogle ScholarPubMed
Hilgier, W., Zielinska, M., Borkowska, H.D., Gadamski, R., Walski, M., Oja, S.S. et al. (1999) Changes in the extracellular profiles of neuroactive amino acids in the rat striatum at the asymptomatic stage of hepatic failure. Journal of Neuroscience Research 56, 76–84; doi:10.1002/(SICI)1097-4547(19990401)56:1 < 76::AID-JNR10 > 3.0.CO;2-Y [pii].3.0.CO;2-Y>CrossRefGoogle ScholarPubMed
Holten, A.T. and Gundersen, V. (2008) Glutamine as a precursor for transmitter glutamate, aspartate and GABA in the cerebellum: a role for phosphate-activated glutaminase. Journal of Neurochemistry 104, 1032–1042; doi:JNC5065 [pii], 10.1111/j.1471-4159.2007.05065.x.CrossRefGoogle ScholarPubMed
Hülsmann, S., Oku, Y., Zhang, W. and Richter, D.W. (2000) Metabolic coupling between glia and neurons is necessary for maintaining respiratory activity in transverse medullary slices of neonatal mouse. European Journal of Neuroscience 12, 856–862; doi:ejn973 [pii].CrossRefGoogle ScholarPubMed
Jenstad, M., Quazi, A.Z., Zilberter, M., Haglerod, C., Berghuis, P., Saddique, N. et al. (2009) System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate. Cerebral Cortex 19, 1092–1106; doi:bhn151 [pii], 10.1093/cercor/bhn151.CrossRefGoogle ScholarPubMed
Jentsch, S. and Schlenker, S. (1995) Selective protein degradation: a journey's end within the proteasome. Cell 82, 881–884; doi:0092-8674(95)90021-7 [pii].CrossRefGoogle ScholarPubMed
Kabra, R., Knight, K.K., Zhou, R. and Snyder, P.M. (2008) Nedd4-2 induces endocytosis and degradation of proteolytically cleaved epithelial Na+ channels. Journal of Biological Chemistry 283, 6033–6039; doi:M708555200 [pii], 10.1074/jbc.M708555200.CrossRefGoogle ScholarPubMed
Kalandadze, A., Wu, Y. and Robinson, M.B. (2002) Protein kinase C activation decreases cell surface expression of the GLT-1 subtype of glutamate transporter. Requirement of a carboxyl-terminal domain and partial dependence on serine 486. Journal of Biological Chemistry 277, 45741–45750; doi:10.1074/jbc.M203771200, M203771200 [pii].CrossRefGoogle ScholarPubMed
Kam, K. and Nicoll, R. (2007) Excitatory synaptic transmission persists independently of the glutamate-glutamine cycle. Journal of Neuroscience 27, 9192–9200; doi:27/34/9192 [pii], 10.1523/JNEUROSCI.1198-07.2007.CrossRefGoogle ScholarPubMed
Kanamori, K. and Ross, B.D. (1995) In vivo activity of glutaminase in the brain of hyperammonaemic rats measured by 15N nuclear magnetic resonance. Biochemical Journal 305, 329–336.CrossRefGoogle ScholarPubMed
Kanamori, K. and Ross, B.D. (2004) Quantitative determination of extracellular glutamine concentration in rat brain, and its elevation in vivo by system A transport inhibitor, alpha-(methylamino)isobutyrate. Journal of Neurochemistry 90, 203–210; doi:10.1111/j.1471-4159.2004.02478.x, JNC2478 [pii].CrossRefGoogle ScholarPubMed
Kanamori, K. and Ross, B.D. (2011) Chronic electrographic seizure reduces glutamine and elevates glutamate in the extracellular fluid of rat brain. Brain Research 1371, 180–191; doi:S0006-8993(10)02577-1 [pii], 10.1016/j.brainres.2010.11.064.CrossRefGoogle ScholarPubMed
Kanamori, K., Ross, B.D. and Kondrat, R.W. (2002) Glial uptake of neurotransmitter glutamate from the extracellular fluid studied in vivo by microdialysis and (13)C NMR. Journal of Neurochemistry 83, 682–695; doi:1161 [pii].CrossRefGoogle Scholar
Kolbaev, S. and Draguhn, A. (2008) Glutamine-induced membrane currents in cultured rat hippocampal neurons. European Journal of Neuroscience 28, 535–545; doi:EJN6365 [pii], 10.1111/j.1460-9568.2008.06365.x.CrossRefGoogle ScholarPubMed
Kosenko, E., Kaminsky, Y., Lopata, O., Muravyov, N., Kaminsky, A., Hermenegildo, C. et al. (1998) Nitroarginine, an inhibitor of nitric oxide synthase, prevents changes in superoxide radical and antioxidant enzymes induced by ammonia intoxication. Metabolic Brain Disease 13, 29–41.CrossRefGoogle ScholarPubMed
Kvamme, E. and Lenda, K. (1982) Regulation of glutaminase by exogenous glutamate, ammonia and 2-oxoglutarate in synaptosomal enriched preparation from rat brain. Neurochemical Research 7, 667–678.CrossRefGoogle ScholarPubMed
Laake, J.H., Slyngstad, T.A., Haug, F.M. and Ottersen, O.P. (1995) Glutamine from glial cells is essential for the maintenance of the nerve terminal pool of glutamate: immunogold evidence from hippocampal slice cultures. Journal of Neurochemistry 65, 871–881.CrossRefGoogle ScholarPubMed
Laake, J.H., Takumi, Y., Eidet, J., Torgner, I.A., Roberg, B., Kvamme, E. et al. (1999) Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum. Neuroscience 88, 1137–1151; doi:S0306-4522(98)00298-X [pii].CrossRefGoogle ScholarPubMed
Lang, F., Henke, G., Embark, H.M., Waldegger, S., Palmada, M., Bohmer, C. et al. (2003) Regulation of channels by the serum and glucocorticoid-inducible kinase – implications for transport, excitability and cell proliferation. Cellular Physiology and Biochemistry 13, 41–50; doi:10.1159/000070248, 70248 [pii].CrossRefGoogle ScholarPubMed
Lebon, V., Petersen, K.F., Cline, G.W., Shen, J., Mason, G.F., Dufour, S. et al. (2002) Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. Journal of Neuroscience 22, 1523–1531; doi:22/5/1523 [pii].CrossRefGoogle ScholarPubMed
Lee, E.S., Sidoryk, M., Jiang, H., Yin, Z. and Aschner, M. (2009) Estrogen and tamoxifen reverse manganese-induced glutamate transporter impairment in astrocytes. Journal of Neurochemistry 110, 530–544; doi:JNC6105 [pii], 10.1111/j.1471-4159.2009.06105.x.CrossRefGoogle ScholarPubMed
Liang, S.L., Carlson, G.C. and Coulter, D.A. (2006) Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. Journal of Neuroscience 26, 8537–8548; doi:26/33/8537 [pii], 10.1523/JNEUROSCI.0329-06.2006.CrossRefGoogle ScholarPubMed
Lucchini, R.G., Martin, C.J. and Doney, B.C. (2009) From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure. Neuromolecular Medicine 11, 311–321; doi:10.1007/s12017-009-8108-8.CrossRefGoogle ScholarPubMed
Mackenzie, B. and Erickson, J.D. (2004) Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflügers Archiv 447, 784–795.CrossRefGoogle ScholarPubMed
Mackenzie, B., Schafer, M.K., Erickson, J.D., Hediger, M.A., Weihe, E. and Varoqui, H. (2003) Functional properties and cellular distribution of the system A glutamine transporter SNAT1 support specialized roles in central neurons. Journal of Biological Chemistry 278, 23720–23730; doi:10.1074/jbc.M212718200, M212718200 [pii].CrossRefGoogle ScholarPubMed
Martin, D.L. (1995) The role of glia in the inactivation of neurotransmitters. In: Kettenmann, H. & Ransom, B.R. (eds) Neuroglia. Oxford University Press, New York, NY, pp. 732–745.Google Scholar
Martinez-Hernandez, A., Bell, K.P. and Norenberg, M.D. (1977) Glutamine synthetase: glial localization in brain. Science 195, 1356–1358.CrossRefGoogle ScholarPubMed
Masson, J., Darmon, M., Conjard, A., Chuhma, N., Ropert, N., Thoby-Brisson, M. et al. (2006) Mice lacking brain/kidney phosphate-activated glutaminase have impaired synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth. Journal of Neuroscience 26, 4660–4671; doi:26/17/4660 [pii], 10.1523/JNEUROSCI.4241-05.2006.CrossRefGoogle ScholarPubMed
Michalak, A., Rose, C., Butterworth, J. and Butterworth, R.F. (1996) Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24, 908–913; doi:S0270913996004284 [pii], 10.1002/hep.510240425.CrossRefGoogle ScholarPubMed
Milatovic, D., Yin, Z., Gupta, R.C., Sidoryk, M., Albrecht, J., Aschner, J.L. et al. (2007) Manganese induces oxidative impairment in cultured rat astrocytes. Toxicological Sciences 98, 198–205; doi:kfm095 [pii], 10.1093/toxsci/kfm095.CrossRefGoogle ScholarPubMed
Mutkus, L., Aschner, J.L., Fitsanakis, V. and Aschner, M. (2005) The in vitro uptake of glutamate in GLAST and GLT-1 transfected mutant CHO-K1 cells is inhibited by manganese. Biological Trace Element Research 107, 221–230; doi:BTER:107:3:221 [pii], 10.1385/BTER:107:3:221.CrossRefGoogle ScholarPubMed
Nissen-Meyer, L.S., Popescu, M.C., Hamdani el, H. and Chaudhry, F.A. (2011) Protein kinase C-mediated phosphorylation of a single serine residue on the rat glial glutamine transporter SN1 governs its membrane trafficking. Journal of Neuroscience 31, 6565–6575; doi:31/17/6565 [pii], 10.1523/JNEUROSCI.3694–10.2011.CrossRefGoogle ScholarPubMed
Nitsch, C., Schmude, B. and Haug, P. (1983) Alterations in the content of amino acid neurotransmitters before the onset and during the course of methoxypyridoxine-induced seizures in individual rabbit brain regions. Journal of Neurochemistry 40, 1571–1580.CrossRefGoogle ScholarPubMed
Obara-Michlewska, M., Pannicke, T., Karl, A., Bringmann, A., Reichenbach, A., Szeliga, M. et al. (2011) Down-regulation of Kir4.1 in the cerebral cortex of rats with liver failure and in cultured astrocytes treated with glutamine: Implications for astrocytic dysfunction in hepatic encephalopathy. Journal of Neuroscience Research doi:10.1002/jnr.22656.CrossRefGoogle ScholarPubMed
Ortinski, P.I., Dong, J., Mungenast, A., Yue, C., Takano, H., Watson, D.J. et al. (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nature Neuroscience 13, 584–591; doi:10.1038/nn.2535.CrossRefGoogle ScholarPubMed
Oz, G., Berkich, D.A., Henry, P.G., Xu, Y., LaNoue, K., Hutson, S.M. et al. (2004) Neuroglial metabolism in the awake rat brain: CO2 fixation increases with brain activity. Journal of Neuroscience 24, 11273–11279; doi:24/50/11273 [pii], 10.1523/JNEUROSCI.3564-04.2004.CrossRefGoogle ScholarPubMed
Palacin, M., Estevez, R., Bertran, J. and Zorzano, A. (1998) Molecular biology of mammalian plasma membrane amino acid transporters. Physiological Reviews 78, 969–1054.CrossRefGoogle ScholarPubMed
Patel, A.B., Rothman, D.L., Cline, G.W. and Behar, K.L. (2001) Glutamine is the major precursor for GABA synthesis in rat neocortex in vivo following acute GABA-transaminase inhibition. Brain Research 919, 207–220; doi:S0006-8993(01)03015-3 [pii].CrossRefGoogle ScholarPubMed
Pellerin, L. and Magistretti, P.J. (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proceedings of the National Academy of Sciences of the U.S.A. 91, 10625–10629.CrossRefGoogle ScholarPubMed
Petroff, O.A., Errante, L.D., Rothman, D.L., Kim, J.H. and Spencer, D.D. (2002) Glutamate-glutamine cycling in the epileptic human hippocampus. Epilepsia 43, 703–710; doi:epi38901 [pii].CrossRefGoogle ScholarPubMed
Plaitakis, A. and Shashidharan, P. (2000) Glutamate transport and metabolism in dopaminergic neurons of substantia nigra: implications for the pathogenesis of Parkinson's disease. Journal of Neurology 247(Suppl 2), II25–II35.CrossRefGoogle ScholarPubMed
Prakash, R. and Mullen, K.D. (2010) Mechanisms, diagnosis and management of hepatic encephalopathy. Nature Reviews. Gastroenterology and Hepatology 7, 515–525; doi:nrgastro.2010.116 [pii], 10.1038/nrgastro.2010.116.CrossRefGoogle ScholarPubMed
Rae, C., Hare, N., Bubb, W.A., McEwan, S.R., Broër, A., McQuillan, J.A. et al. (2003) Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation. Journal of Neurochemistry 85, 503–514; doi:1713 [pii].CrossRefGoogle ScholarPubMed
Reubi, J.C., Van Der Berg, C. and Cuenod, M. (1978) Glutamine as precursor for the GABA and glutamate trasmitter pools. Neuroscience Letters 10, 171–174; doi:0304-3940(78)90030-7 [pii].CrossRefGoogle ScholarPubMed
Rhoads, M. (1999) Glutamine signaling in intestinal cells. Journal of Parenteral and Enteral Nutrition 23(5 Suppl), S38–S40.CrossRefGoogle ScholarPubMed
Rosati, A., Marconi, S., Pollo, B., Tomassini, A., Lovato, L., Maderna, E. et al. (2009) Epilepsy in glioblastoma multiforme: correlation with glutamine synthetase levels. Journal of Neuro-Oncology 93, 319–324; doi:10.1007/s11060-008-9794-z.CrossRefGoogle ScholarPubMed
Roth, J.A. and Garrick, M.D. (2003) Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese. Biochemical Pharmacology 66, 1–13; doi:S000629520300145X [pii].CrossRefGoogle ScholarPubMed
Rothman, D.L., Sibson, N.R., Hyder, F., Shen, J., Behar, K.L. and Shulman, R.G. (1999) In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philosophical Transactions of the Royal Society B: Biological Sciences 354, 1165–1177.CrossRefGoogle ScholarPubMed
Ryan, R.M. and Vandenberg, R.J. (2002) Distinct conformational states mediate the transport and anion channel properties of the glutamate transporter EAAT-1. Journal of Biological Chemistry 277, 13494–13500; doi:10.1074/jbc.M109970200, M109970200 [pii].CrossRefGoogle ScholarPubMed
Sandow, J. (2009) Growth effects of insulin and insulin analogues. Archives of Physiology and Biochemistry 115, 72–85; doi:10.1080/13813450902835690.CrossRefGoogle ScholarPubMed
Schliess, F., Gorg, B., Fischer, R., Desjardins, P., Bidmon, H.J., Herrmann, A. et al. (2002) Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes. FASEB Journal 16, 739–741; doi:10.1096/fj.01-0862fje, 01-0862fje [pii].CrossRefGoogle ScholarPubMed
Schneider, H.P., Broër, S., Broër, A. and Deitmer, J.W. (2007) Heterologous expression of the glutamine transporter SNAT3 in Xenopus oocytes is associated with four modes of uncoupled transport. Journal of Biological Chemistry 282, 3788–3798; doi:M609452200 [pii], 10.1074/jbc.M609452200.CrossRefGoogle ScholarPubMed
Schousboe, A., Westergaard, N., Sonnewald, U., Petersen, S.B., Huang, R., Peng, L. et al. (1993) Glutamate and glutamine metabolism and compartmentation in astrocytes. Developmental Neuroscience 15, 359–366.CrossRefGoogle ScholarPubMed
Shank, R.P. and Campbell, G.L. (1984) Alpha-ketoglutarate and malate uptake and metabolism by synaptosomes: further evidence for an astrocyte-to-neuron metabolic shuttle. Journal of Neurochemistry 42, 1153–1161.CrossRefGoogle ScholarPubMed
Shen, J., Petersen, K.F., Behar, K.L., Brown, P., Nixon, T.W., Mason, G.F. et al. (1999) Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR. Proceedings of the National Academy of Sciences of the U.S.A. 96, 8235–8240.CrossRefGoogle ScholarPubMed
Sibson, N.R., Dhankhar, A., Mason, G.F., Behar, K.L., Rothman, D.L. and Shulman, R.G. (1997) In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling. Proceedings of the National Academy of Sciences of the U.S.A. 94, 2699–2704.CrossRefGoogle ScholarPubMed
Sibson, N.R., Shen, J., Mason, G.F., Rothman, D.L., Behar, K.L. and Shulman, R.G. (1998) Functional energy metabolism: in vivo 13C-NMR spectroscopy evidence for coupling of cerebral glucose consumption and neuronalactivity. Developmental Neuroscience 20, 321–330; doi:dne20321 [pii].CrossRefGoogle ScholarPubMed
Sidoryk-Wegrzynowicz, M., Lee, E., Albrecht, J. and Aschner, M. (2009) Manganese disrupts astrocyte glutamine transporter expression and function. Journal of Neurochemistry 110, 822–830; doi:JNC6172 [pii], 10.1111/j.1471-4159.2009.06172.x.CrossRefGoogle ScholarPubMed
Sidoryk-Wegrzynowicz, M., Lee, E.S., Ni, M. and Aschner, M. (2010) Manganese-induced downregulation of astroglial glutamine transporter SNAT3 involves ubiquitin-mediated proteolytic system. Glia 58, 1905–1912; doi:10.1002/glia.21060.CrossRefGoogle ScholarPubMed
Solbu, T.T., Bjorkmo, M., Berghuis, P., Harkany, T. and Chaudhry, F.A. (2010) SAT1, a glutamine transporter, is preferentially expressed in GABAergic neurons. Frontiers in Neuroanatomy 4, 1; doi:10.3389/neuro.05.001.2010.Google ScholarPubMed
Sonnewald, U., Westergaard, N., Schousboe, A., Svendsen, J.S., Unsgard, G. and Petersen, S.B. (1993) Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochemistry International 22, 19–29.CrossRefGoogle ScholarPubMed
Spadoni, F., Stefani, A., Morello, M., Lavaroni, F., Giacomini, P. and Sancesario, G. (2000) Selective vulnerability of pallidal neurons in the early phases of manganese intoxication. Experimental Brain Research 135, 544–551.CrossRefGoogle ScholarPubMed
Steffens, M., Huppertz, H.J., Zentner, J., Chauzit, E. and Feuerstein, T.J. (2005) Unchanged glutamine synthetase activity and increased NMDA receptor density in epileptic human neocortex: implications for the pathophysiology of epilepsy. Neurochemistry International 47, 379–384; doi:S0197-0186(05)00147-6 [pii], 10.1016/j.neuint.2005.06.001.CrossRefGoogle ScholarPubMed
Storm-Mathisen, J., Ottersen, O.P., Fu-Long, T., Gundersen, V., Laake, J.H. and Nordbo, G. (1986) Metabolism and transport of amino acids studied by immunocytochemistry. Medical Biology 64, 127–132.Google ScholarPubMed
Stumpo, R.J., Pullan, L.M. and Salama, A.I. (1989) Glutamine mimics glycine to enhance [3H]TCP binding at the NMDA receptor complex. European Journal of Pharmacology 170, 121–122; doi:0014-2999(89)90147-7 [pii].CrossRefGoogle ScholarPubMed
Sugimoto, H., Koehler, R.C., Wilson, D.A., Brusilow, S.W. and Traystman, R.J. (1997) Methionine sulfoximine, a glutamine synthetase inhibitor, attenuates increased extracellular potassium activity during acute hyperammonemia. Journal of Cerebral Blood Flow and Metabolism 17, 44–49; doi:10.1097/00004647-199701000-00006.CrossRefGoogle ScholarPubMed
Szeliga, M. and Obara-Michlewska, M. (2009) Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. Neurochemistry International 55, 71–75; doi:S0197-0186(09)00028-X [pii], 10.1016/j.neuint.2009.01.008.CrossRefGoogle ScholarPubMed
Szerb, J.C. (1984) Storage and release of endogenous and labelled GABA formed from [3H]glutamine and [14C]glucose in hippocampal slices: effect of depolarization. Brain Research 293, 293–303; doi:0006-8993(84)91236–8 [pii].CrossRefGoogle ScholarPubMed
Szerb, J.C. and O'Regan, P.A. (1985) Effect of glutamine on glutamate release from hippocampal slices induced by high K+ or by electrical stimulation: interaction with different Ca2+ concentrations. Journal of Neurochemistry 44, 1724–1731.CrossRefGoogle ScholarPubMed
Tani, H., Bandrowski, A.E., Parada, I., Wynn, M., Huguenard, J.R., Prince, D.A. et al. (2007) Modulation of epileptiform activity by glutamine and system A transport in a model of post-traumatic epilepsy. Neurobiology of Disease 25, 230–238; doi:S0969-9961(06)00220-8 [pii], 10.1016/j.nbd.2006.08.025.CrossRefGoogle Scholar
Tani, H., Dulla, C.G., Huguenard, J.R. and Reimer, R.J. (2010) Glutamine is required for persistent epileptiform activity in the disinhibited neocortical brain slice. Journal of Neuroscience 30, 1288–1300; doi:30/4/1288 [pii], 10.1523/JNEUROSCI.0106-09.2010.CrossRefGoogle ScholarPubMed
Tapia, R. and Gonzalez, R.M. (1978) Glutamine and glutamate as precursors of the releasable pool of gaba in brain cortex slices. Neuroscience Letters 10, 165–169; doi:0304-3940(78)90029-0 [pii].CrossRefGoogle ScholarPubMed
Thanki, C.M., Sugden, D., Thomas, A.J. and Bradford, H.F. (1983) In vivo release from cerebral cortex of [14C]glutamate synthesized from [U-14C]glutamine. Journal of Neurochemistry 41, 611–617.CrossRefGoogle ScholarPubMed
Tofteng, F., Hauerberg, J., Hansen, B.A., Pedersen, C.B., Jorgensen, L. and Larsen, F.S. (2006) Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. Journal of Cerebral Blood Flow and Metabolism 26, 21–27; doi:9600168 [pii], 10.1038/sj.jcbfm.9600168.CrossRefGoogle ScholarPubMed
Tossman, U., Delin, A., Eriksson, L.S. and Ungerstedt, U. (1987) Brain cortical amino acids measured by intracerebral dialysis in portacaval shunted rats. Neurochemical Research 12, 265–269.CrossRefGoogle ScholarPubMed
Van den Berg, C.J. (1972) A model of compartmentation in mouse brain based on glucose and acetate metabolism. In Balazs, R. & Cremer, J.E. (eds) Metabolic Compartmentation in the Brain. John Wiley & Sons, New York, NY, pp. 137–166.Google Scholar
Vogels, B.A., van Steynen, B., Maas, M.A., Jorning, G.G. and Chamuleau, R.A. (1997) The effects of ammonia and portal-systemic shunting on brain metabolism, neurotransmission and intracranial hypertension in hyperammonaemia-induced encephalopathy. Journal of Hepatology 26, 387–395.CrossRefGoogle ScholarPubMed
Waagepetersen, H.S., Qu, H., Sonnewald, U., Shimamoto, K. and Schousboe, A. (2005) Role of glutamine and neuronal glutamate uptake in glutamate homeostasis and synthesis during vesicular release in cultured neurons. Neurochemistry International 47, 92–102; doi:S0197-0186(05)00097-5 [pii], 10.1016/j.neuint.2005.04.012.CrossRefGoogle Scholar
Waagepetersen, H.S., Sonnewald, U., Gegelashvili, G., Larsson, O.M. and Schousboe, A. (2001) Metabolic distinction between vesicular and cytosolic GABA in cultured GABAergic neurons using 13C magnetic resonance spectroscopy. Journal of Neuroscience Research 63, 347–355; doi:10.1002/1097-4547(20010215)63:4 < 347::AID-JNR1029 > 3.0.CO;2-G [pii].3.0.CO;2-G>CrossRefGoogle ScholarPubMed
Wang, L., Maher, T.J. and Wurtman, R.J. (2007) Oral L-glutamine increases GABA levels in striatal tissue and extracellular fluid. FASEB Journal 21, 1227–1232; doi:fj.06-7495com [pii], 10.1096/fj.06-7495com.CrossRefGoogle ScholarPubMed
Waniewski, R.A. and Martin, D.L. (1986) Exogenous glutamate is metabolized to glutamine and exported by rat primary astrocyte cultures. Journal of Neurochemistry 47, 304–313.CrossRefGoogle ScholarPubMed
Ward, H.K., Thanki, C.M. and Bradford, H.F. (1983) Glutamine and glucose as precursors of transmitter amino acids: ex vivo studies. Journal of Neurochemistry 40, 855–860.CrossRefGoogle ScholarPubMed
Weiss, B. (2006) Economic implications of manganese neurotoxicity. Neurotoxicology 27, 362–368; doi:S0161-813X(05)00030-6 [pii], 10.1016/j.neuro.2005.03.011.CrossRefGoogle ScholarPubMed
Westergaard, N., Sonnewald, U. and Schousboe, A. (1995) Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. Developmental Neuroscience 17, 203–211.CrossRefGoogle ScholarPubMed
Xu, G.Y., McAdoo, D.J., Hughes, M.G., Robak, G. and de Castro, R. Jr. (1998) Considerations in the determination by microdialysis of resting extracellular amino acid concentrations and release upon spinal cord injury. Neuroscience 86, 1011–1021; doi:S0306-4522(98)00063-3 [pii].CrossRefGoogle ScholarPubMed
Yamada, K.A. and Rothman, S.M. (1989) Glutamine currents in hippocampal neurons are attributable to contaminating glutamate. Brain Research 498, 351–354; doi:0006-8993(89)91115-3 [pii].CrossRefGoogle ScholarPubMed
Zhang, Z. and Grewer, C. (2007) The sodium-coupled neutral amino acid transporter SNAT2 mediates an anion leak conductance that is differentially inhibited by transported substrates. Biophysical Journal 92, 2621–2632; doi:S0006-3495(07)71065-2 [pii], 10.1529/biophysj.106.100776.CrossRefGoogle ScholarPubMed
Zhou, R., Patel, S.V. and Snyder, P.M. (2007) Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC. Journal of Biological Chemistry 282, 20207–20212; doi:M611329200 [pii], 10.1074/jbc.M611329200.CrossRefGoogle ScholarPubMed
Zielińska, M., Ruszkiewicz, J., Hilgier, W., Fresko, I. and Albrecht, J. (2011) Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y+ LAT2 in rat cerebral cortex: implications for the nitric oxide/cGMP pathway. Neurochemistry International 58, 190–195; doi:S0197-0186(10)00355-4 [pii], 10.1016/j.neuint.2010.11.015.CrossRefGoogle ScholarPubMed