The GABA paradox: Multiple roles as metabolite, neurotransmitter, and neurodifferentiative agent

Journal of Neurochemistry

Volumn 73, Issue 4, 1999, Pages 1335-1342

  Waagepetersen, Helle S ^a   Sonnewald, Ursula ^b   Schousboe, Arne ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Norway)

Author keywords

Compartmentation; Epilepsy; Glutamate; Glutamate decarboxylase; Glutamine; Metabolism; Mitochondria; Tricarboxylic acid cycle

Indexed keywords

4 AMINOBUTYRIC ACID; GLUTAMATE DECARBOXYLASE; GLUTAMINE;

4 AMINOBUTYRIC ACID METABOLISM; AMINO ACID SYNTHESIS; BRAIN MITOCHONDRION; CITRIC ACID CYCLE; EPILEPSY; HUMAN; NERVE CELL DIFFERENTIATION; NEUROTRANSMISSION; NONHUMAN; PRIORITY JOURNAL; SHORT SURVEY;

ANIMALS; BRAIN; CELL DIFFERENTIATION; EPILEPSY; GAMMA-AMINOBUTYRIC ACID; GLUTAMATE DECARBOXYLASE; GLUTAMINE; HUMANS; ISOENZYMES; NEURONS; SYNAPTIC TRANSMISSION;

EID: 0032842197     PISSN: 00223042     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1471-4159.1999.0731335.x     Document Type: Short Survey

References (97)

1. Balázs R., Machiyama Y., Hammond B. J., Julian T., and Richter D. (1970) The operation of the gamma-aminobutyrate bypath of the tricarboxylic acid cycle in brain tissue in vitro. Biochem. J. 116, 445-461.
2. Battaglioli G. and Martin D. L. (1990) Stimulation of synaptosomal γ-aminobutyric acid synthesis by glutamate and glutamine. J. Neurochem. 54, 1179-1187.
3. Battaglioli G. and Martin D. L. (1996) Glutamine stimulates γ-aminobutyric acid synthesis in synaptosomes but other putative astrocyte-to-neuron shuttle substrates do not. Neurosci. Lett. 209, 129-133.
4. Belhage B., Meier E., and Schousboe A. (1986) GABA-agonists induce the formation of low-affinity GABA-receptors on cultured cerebellar granule cells via preexisting high affinity GABA-receptors. Neurochem. Res. 11, 599-606.
5. Belhage B., Hansen G. H., Meier E., and Schousboe A. (1990) Effects of inhibitors of protein synthesis and intracellular transport on the γ-aminobutyric acid agonist-induced functional differentiation of cultured cerebellar granule cells. J. Neurochem. 55, 1107-1113.
6. + and glutamate activates different neurotransmitter release mechanisms in GABAergic neurons: vesicular versus non-vesicular release of GABA. Neuroscience 54, 1019-1034.
7. Belhage B., Hansen G. H., Elster L., and Schousboe A. (1998) Effects of gamma-aminobutyric acid (GABA) on synaptogenesis and synaptic function. Perspect. Dev. Neurobiol. 5, 235-246.
8. Bernasconi R., Maitre L., Martin P., and Raschdorf F. (1982) The use of inhibitors of GABA-transaminase for the determination of GABA turnover in mouse brain regions: an evaluation of aminooxyacetic acid and gabaculine. J. Neurochem. 38, 57-66.
9. Borden L. A. (1996) GABA transporter heterogeneity: pharmacology and cellular localization. Neurochem. Int. 29, 335-356.
10. Braestrup C., Nielsen E. B., Sonnewald U., Knutsen L. J., Andersen K. E., Jansen J. A., Frederiksen K., Andersen P. H., Mortensen A., and Suzdak P. D. (1990) (R)-N-[4,4-Bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid binds with high affinity to the brain γ-aminobutyric acid uptake carrier. J. Neurochem. 54, 639-647.
11. Bu D.-F., Erlander M. G., Hitz B. C., Tillakaratne N. J. K., Kaufman D. L., Wagner-McPherson C. B., Evans B. A., and Tobin A. J. (1992) Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc. Natl. Acad. Sci. USA 89, 2115-2119.
12. Carlson B. X., Elster L., and Schousboe A. (1998) Pharmacological and functional implications of developmentally-regulated changes in GABA(A) receptor subunit expression in the cerebellum. Eur. J. Pharmacol. 352, 1-14.
13. Cesar M. and Hamprecht B. (1995) Immunohistochemical examination of neural rat and mouse primary cultures using monoclonal antibodies raised against pyruvate carboxylase. J. Neurochem. 64, 2312-2318.
14. Chapman A. G. and Evans M. C. (1983) Cortical GABA turnover during bicuculline seizures in rats. J. Neurochem. 41, 886-889.
15. De Mello F. G., Bachrach U., and Nirenberg M. (1976) Ornithine and glutamate decarboxylase activities in developing chick retina. J. Neurochem. 27, 847-851.
16. Drejer J., Larsson O. M., Kvamme E., Svenneby G., Hertz L., and Schousboe A. (1985) Ontogenetic development of glutamate metabolizing enzymes in cultured cerebellar granule cells and in cerebellum in vivo. Neurochem. Res. 10, 49-62.
17. During M. J., Ryder K. M., and Spencer D. D. (1995) Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 376, 174-177.
18. Erlander M. G., Tillakaratne N. J. K., Feldblum S., Patel N., and Tobin A. J. (1991) Two genes encode distinct glutamate decarboxylases. Neuron 7, 91-100.
19. Fink-Jensen A., Suzdak P. D., Swedberg M. D., Judge M. E., Hansen L., and Nielsen P. G. (1992) The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats. Eur. J. Pharmacol. 220, 197-201.
20. Gale K., Iadarola M. J., Casu M., and Keating R. F. (1982) Relationship between GABA levels in vivo and anticonvulsant activity: importance of cellular compartments and regional localization in brain, in Problems in GABA Research from Brain to Bacteria (Okada Y. and Roberts E., eds), pp. 159-181. Excerpta Medica, Amsterdam.
21. Garfinkel D. (1966) A simulation study of the metabolism and compartmentation in brain of glutamate, aspartate, the Krebs cycle, and related metabolites. J. Biol. Chem. 241, 3918-3929.
22. Golan H. and Grossman Y. (1996) Block of glutamate decarboxylase decreases GABAergic inhibition at the crayfish synapses: possible role of presynaptic metabotropic mechanisms. J. Neurophysiol. 75, 2089-2098.
23. Golan H., Talpalar A. E., Schleifstein-Attias D., and Grossman Y. (1996) GABA metabolism controls inhibition efficacy in the mammalian CNS. Neurosci. Lett. 217, 25-28.
24. r 67,000) in the basal ganglia of the rat: an immunohistochemical study with a selective cDNA-generated polyclonal antibody. J. Neurocytol. 20, 953-961.
25. 3H]GABA by growth cones isolated from neonatal rat brain. Neurosci. Lett. 52, 205-210.
26. Gram L., Larsson O. M., Johnsen A. H., and Schousboe A. (1988) Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons. Epilepsy Res. 2, 87-95.
27. Hassel B., Johannessen C. U., Sonnewald U., and Fonnum F. (1998) Quantification of the GABA shunt and the importance of the GABA shunt versus the 2-oxoglutarate dehydrogenase pathway in GABAergic neurons. J. Neurochem. 71, 1511-1518.
28. Henry S. and Tappaz M. (1991) Relative enrichment of the lighter 59 kDa form of glutamic acid decarboxylase in nerve endings: an immunoblotting study in pituitary neurointermediate lobe. Neurosci. Lett. 131, 253-256.
29. Hertz L. and Schousboe A. (1987) Primary cultures of GABAergic and glutamatergic neurons as model systems to study neurotransmitter functions. I. Differentiated cells, in Model Systems of Development and Aging of the Nervous System (Vernadakis A., Privat A., Lauder J. M., Timiras P. S., and Giacobini E., eds), pp. 19-31. Martinus Nijhoff Publishing, Boston.
30. Hertz L., Yu A. C., and Schousboe A. (1992) Uptake and metabolism of malate in neurons and astrocytes in primary cultures. J. Neurosci. Res. 33, 289-296.
31. Hokoc J. N., Ventura A. L., Gardino P. F., and De Mello F. G. (1990) Developmental immunoreactivity for GABA and GAD in the avian retina: possible alternative pathway for GABA synthesis. Brain Res. 532, 197-202.
32. Iadarola M. J. and Gale K. (1980) Evaluation of increases in nerve terminal-dependent vs. nerve terminal-independent compartments of GABA in vivo. Brain Res. Bull. 5, S213-S219.
33. Iadarola M. J. and Gale K. (1981) Cellular compartments of GABA in brain and their relationship to anticonvulsant activity. Mol. Cell. Biochem. 39, 305-330.
34. Kaufman D. L., McGinnes J. F., Krieger N. R., and Tobin A. J. (1986) Brain glutamate decarboxylase cloned in λgt-11: fusion protein produces γ-aminobutyric acid. Science 232, 1138-1140.
35. Kaufman D. L., Houser C. R., and Tobin A. J. (1991) Two forms of the γ-aminobutyric acid synthetic enzyme-glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J. Neurochem. 56, 720-723.
36. Kihara M. and Kubo T. (1989) Aspartate aminotransferase for synthesis of transmitter glutamate in the medulla oblongata: effect of aminooxyacetic acid and 2-oxoglutarate. J. Neurochem. 52, 1127-1134.
37. Kobayashi Y., Kaufman D. L., and Tobin A. J. (1987) Glutamic acid decarboxylase cDNA: nucleotide sequence encoding an enzymatically active fusion protein. J. Neurosci. 7, 2768-2772.
38. Kvamme E., Svenneby G., and Torgner I. A. (1988) Glutaminases, in Glutamine and Glutamate in Mammals, Vol. 2 (Kvamme E., ed), pp. 54-63. CRC Press, Boca Raton, Florida.
39. Laake J. H., Takumi Y., Eidet J., Torgner I. A., Roberg B., Kvamme E., and Ottersen O. P. (1999) Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum. Neuroscience 88, 1137-1151.
40. Larsson O. M., Drejer J., Kvamme E., Svenneby G., Hertz L., and Schousboe A. (1985) Ontogenetic development of glutamate and GABA metabolizing enzymes in cultured cerebral cortex interneurons and in cerebral cortex in vivo. Int. J. Dev. Neurosci. 3, 177-185.
41. Larsson O. M., Gram L., Schousboe I., and Schousboe A. (1986) Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurones and astrocytes. Neuropharmacology 25, 617-625.
42. Liden E., Karlson I., and Sellstrom A. (1987) Is the concentration of γ-aminobutyric acid in the nerve terminal regulated via product inhibition of glutamic acid decarboxylase? Neurochem. Res. 12, 489-493.
43. Martin D. L. and Rimvall K. (1993) Regulation of γ-aminobutyric acid synthesis in the brain. J. Neurochem. 60, 395-407.
44. Martin D. L., Martin S. B., Wu S. J., and Espina N. (1991a) Cofactor interactions and the regulation of glutamate decarboxylase activity. Neurochem. Res. 16, 243-249.
45. Martin D. L., Martin S. B., Wu S. J., and Espina N. (1991b) Regulatory properties of brain glutamate decarboxylase (GAD): the apoenzyme of GAD is present principally as the smaller of two molecular forms of GAD in brain. J. Neurosci. 11, 2725-2731.
46. Mason G. F., Gruetter R., Rothman D. L., Behar K. L., Shulman R. G., and Novotny E. J. (1995) Simultaneous determination of the rates of the TCA cycle, glucose utilization, alpha-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR. J. Cereb. Blood Flow Metab. 15, 12-25.
47. Matsuda T., Wu J.-Y., and Roberts E. (1973) Electrophoresis of glutamic acid decarboxylase (EC 4.1.1.15) from mouse brain in sodium dodecyl sulphate polyacrylamide gels. J. Neurochem. 21, 167-172.
48. McGeer E. G., McGeer P. L., and Thompson S. (1983) GABA and glutamate enzymes, in Glutamine, Glutamate and GABA in the Central Nervous System (Hertz L., Kvamme E., McGeer E. G., and Schousboe A., eds), pp. 3-17. Alan R. Liss, Inc., New York.
49. Meier E., Hansen G. H., and Schousboe A. (1985) The trophic effect of GABA on cerebellar granule cells is mediated by GABA-receptors. Int. J. Dev. Neurosci. 3, 401-407.
50. Meier E., Hertz L., and Schousboe A. (1991) Neurotransmitters as developmental signals. Neurochem. Int. 19, 1-15.
51. Minelli A., Brecha N. C., Karschin C., DeBiasi S., and Conti F. (1995) GAT-1, a high-affinity GABA plasma membrane transporter, is localized to neurons and astroglia in the cerebral cortex. J. Neurosci. 15, 7734-7746.
52. Nishimura M., Sato K., Mizuno M., Yoshiya I., Shimada S., Saito N., and Tohyama M. (1997) Differential expression patterns of GABA transporters (GAT1-3) in the rat olfactory bulb. Brain Res. Mol. Brain Res. 45, 268-274.
53. Norenberg M. D. and Martinez-Hernandez A. (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res. 161, 303-310.
54. Patel A. J., Johnson A. L., and Balázs R. (1974) Metabolic compartmentation of glutamate associated with the formation of γ-aminobutyrate. J. Neurochem. 23, 1271-1279.
55. Paulsen R. and Fonnum F. (1987) Comparison of results obtained with different methods for estimating GABA turnover in rat neostriatum. Biochem. Pharmacol. 36, 1539-1544.
56. Porter T. G. and Martin D. L. (1984) Evidence for feedback regulation of glutamate decarboxylase by γ-aminobutyric acid. J. Neurochem. 43, 1464-1467.
57. Preece N. E. and Cerdan S. (1996) Metabolic precursors and compartmentation of cerebral GABA in vigabatrin-treated rats. J. Neurochem. 67, 1718-1725.
58. Reubi J. C., Van den Berg C. J., and Cuénod M. (1978) Glutamine as precursor for the GABA and glutamate transmitter pools. Neurosci. Lett. 10, 171-174.
59. Roberts E. (1991) Living systems are tonically inhibited, autonomous optimizers, and disinhibition coupled to variability generation is their major organizing principle: inhibitory command-control at levels of membrane, genome, metabolism, brain, and society. Neurochem. Res. 16, 409-421.
60. Roberts E. and Bregoff H. M. (1953) Transamination of γ-aminobutyric acid and β-alanine in brain and liver. J. Biol. Chem. 201, 393-398.
61. Roberts E. and Frankel S. (1950) γ-Aminobutyric acid in brain: its formation from glutamic acid. J. Biol. Chem. 187, 55-63.
62. Roepstorff A. and Lambert J. D. (1992) Comparison of the effect of the GABA uptake blockers, tiagabine and nipecotic acid, on inhibitory synaptic efficacy in hippocampal CA1 neurones. Neurosci. Lett. 146, 131-134.
63. Salganicoff L. and De Robertis E. (1965) Subcellular distribution of the enzymes of the glutamic acid, glutamine and γ-aminobutyric acid cycles in rat brain. J. Neurochem. 12, 287-309.
64. Schousboe A. (1990) Neurochemical alterations associated with epilepsy or seizure activity, in Comprehensive Epileptology (Dam M. and Gram L., eds), pp. 1-16. Raven Press, New York.
65. Schousboe A. and Redburn D. A. (1995) Modulatory actions of gamma aminobutyric acid (GABA) on GABA type A receptor subunit expression and function. J. Neurosci. Res. 41, 1-7.
66. Schousboe A., Wu J. Y., and Roberts E. (1973) Purification and characterization of the 4-aminobutyrate-2,ketoglutarate transaminase from mouse brain. Biochemistry 12, 2868-2873.
67. Schousboe A., Svenneby G., and Hertz L. (1977) Uptake and metabolism of glutamate in astrocytes cultured from dissociated mouse brain hemispheres. J. Neurochem. 29, 999-1005.
68. Schousboe A., Larsson O. M., Hertz L., and Krogsgaard-Larsen P. (1981) Heterocyclic GABA analogues as selective inhibitors of astroglial GABA uptake. Adv. Biochem. Psychopharmacol. 29, 135-141.
69. Schousboe A., Westergaard N., Sonnewald U., Petersen S. B., Huang R., Peng L., and Hertz L. (1993) Glutamate and glutamine metabolism and compartmentation in astrocytes. Dev. Neurosci. 15, 359-366.
70. Schwarzer C. and Sperk G. (1995) Hippocampal granule cells express glutamic acid decarboxylase-67 after limbic seizures in the rat. Neuroscience 69, 705-709.
71. Seiler N. (1980) On the role of GABA in vertebrate polyamine metabolism. Physiol. Chem. Phys. 12, 411-429.
72. Shank R. P. and Campbell G. L. (1984) α-Ketoglutarate and malate uptake and metabolism by synaptosomes: further evidence for an astrocytes-to-neuron metabolic shuttle. J. Neurochem. 42, 1153-1161.
73. Shank R. P. and Reife R. A. (1999) Agents for the treatment of epilepsy, in Quick Look: Pharmacology (Raffa R., ed), in press. Fence Creek Publishing, Lyndell, Pennsylvania.
74. Shank R. P., Bennett G. S., Freytag S. O., and Campbell G. L. (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res. 329, 364-367.
75. Shank R. P., Baldy W. J., and Ash C. W. (1989) Glutamine and 2-oxoglutarate as metabolic precursors of the transmitter pools of glutamate and GABA: correlation of regional uptake by rat brain synaptosomes. Neurochem. Res. 4, 371-376.
76. Sheikh S. N. and Martin D. L. (1998) Elevation of brain GABA levels with vigabatrin (gamma-vinyl GABA) differentially affects GAD65 and GAD67 expression in various regions of rat brain. J. Neurosci. Res. 52, 736-741.
77. Sihra T. S. and Nicholls D. G. (1987) γ-Aminobutyrate can be released exocytotically from guinea-pig cerebral cortical synaptosomes. J. Neurochem. 49, 261-267.
78. Sloviter R. S., Dichter M. A., Rachinsky T. L., Dean E., Goodman J. H., Sollas A. L., and Martin D. L. (1996) Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J. Comp. Neurol. 373, 593-618.
79. 14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 28, 897-916.
80. 13C glucose metabolism in neocortical astrocytes: evidence for mitochondrial heterogeneity. Dev. Neurosci. 15, 351-358.
81. 13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem. Int. 1, 19-29.
82. Sonnewald U., Hertz L., and Schousboe A. (1998) Mitochondrial heterogeneity in the brain at the cellular level. J. Cereb. Blood Flow Metab. 18, 231-237.
83. Tapia R. (1975) Biochemical pharmacology in CNS, in Handbook of Psychopharmacology, Vol. 4 (Iversen L. L., Iversen S. D., and Snyder S. H., eds), pp. 1-58. Plenum Press, New York.
84. 13C-NMR spectroscopy. J. Cereb. Blood Flow Metab. 18, 109-117.
85. 13C NMR spectroscopy. Dev. Neurosci. 20, 310-320.
86. Waagepetersen H. S., Sonnewald U., Larsson O. M., and Schousboe A. (1999a) Synthesis of vesicular GABA from glutamine involves TCA cycle metabolism in neocortical neurons. J. Neurosci. Res. 57, 342-349.
87. 13C MR spectroscopy. Neurochem. Int. (in press).
88. Westergaard N., Larsson O. M., Jensen B., and Schousboe A. (1992) Synthesis and release of GABA in cerebral cortical neurons co-cultured with astrocytes from cerebral cortex or cerebellum. Neurochem. Int. 20, 567-575.
89. 13C NMR spectroscopy may indicate compartmentation and mitochondrial heterogeneity. Neurosci. Lett. 185, 24-28.
90. Westergaard N., Sonnewald U., and Schousboe A. (1995b) Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. Dev. Neurosci. 17, 203-211.
91. Wolff J. R., Joo F., and Dames W. (1978) Plasticity in dendrites shown by continuous GABA administration in superior cervical ganglion of adult rat. Nature 274, 72-74.
92. Wood J. D. and Kurylo E. (1980) Drug induced changes in the GABA content of nerve terminals determined using a synaptosomal model. Brain Res. Bull. 5, S925-S927.
93. Wu J.-Y., Matsuda T., and Roberts E. (1973) Purification and characterization of glutamate decarboxylase from mouse brain. J. Biol. Chem. 248, 3029-3034.
94. 67) mRNA localization. Brain Res. Mol. Brain Res. 44, 205-218.
95. Yu A. C. H., Drejer J., Hertz L., and Schousboe A. (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J. Neurochem. 41, 1484-1487.
96. 14C]-glutamine in mouse cerebral neurons in primary cultures. J. Neurosci. Res, 11, 351-357.
97. 15N]glutamine. J. Neurochem. 53, 632-640.