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. 1978 Jun;75(6):2981–2985. doi: 10.1073/pnas.75.6.2981

Modulation of γ-aminobutyric acid transport in nerve endings: Role of extracellular γ-aminobutyric acid and of cationic fluxes

Giulio Levi *, Maurizio Raiteri
PMCID: PMC392691  PMID: 351622

Abstract

The aim of the present study was to elucidate the possible functional significance of γ-aminobutyric acid (GABA) homoexchange at nerve endings. Using synaptosomes from adult rat cerebrum, we found that a number of conditions altering cationic fluxes produced a concomitant change in the stoichiometry of GABA homoexchange, In fact, exogenous GABA (10 μM), while not causing net release of intrasynaptosomal GABA in standard conditions, triggered a large net GABA release in the presence of veratridine, Na+-K+-ATPase inhibitors, or the ionophore A23187, superimposed on that due to the various agents tested alone. This extra release was mediated by the membrane carrier, being largely inhibited by the GABA carrier-blocker L-diaminobutyric acid. The altered stoichiometry of GABA homoexchange observed under these conditions (efflux > influx) appeared to be coupled to the influx of Na+ (or of Ca2+), rather than determined by the establishment of a high intrasynaptosomal [Na+]. Under conditions of reversed Na+ flux (Na+ efflux), the GABA outward/inward flux ratio was also reversed, and the stoichiometry of GABA homoexchange was in favor of net influx. The possible contribution of K+ to the effects observed is also discussed. It is concluded that the GABA transport system of nerve endings is susceptible to fine modulation by changes in cationic fluxes similar to those occurring in vivo during depolarization and repolarization. These fluxes may have a prominent role in determining the direction of net GABA transport in GABA-ergic nerve terminals of the living brain.

Keywords: neurotransmitters, synaptosomes, transmitter release, transmitter amino acids, homoexchange

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Selected References

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  1. Archibald J. T., White T. D. Rapid reversal of internal Na+ and K+ contents of synaptosomes by ouabain. Nature. 1974 Dec 13;252(5484):595–596. doi: 10.1038/252595a0. [DOI] [PubMed] [Google Scholar]
  2. Axelrod J. The fate of noradrenaline in the sympathetic neurone. Harvey Lect. 1973;67:175–197. [PubMed] [Google Scholar]
  3. Banay-Schwartz M., Teller D. N., Lajtha A. Energetics of low affinity amino acid transport into brain slices. Adv Exp Med Biol. 1976;69:349–370. doi: 10.1007/978-1-4684-3264-0_26. [DOI] [PubMed] [Google Scholar]
  4. Blaustein M. P. Effects of potassium, veratridine, and scorpion venom on calcium accumulation and transmitter release by nerve terminals in vitro. J Physiol. 1975 Jun;247(3):617–655. doi: 10.1113/jphysiol.1975.sp010950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blaustein M. P., Oborn C. J. The influence of sodium on calcium fluxes in pinched-off nerve terminals in vitro. J Physiol. 1975 Jun;247(3):657–686. doi: 10.1113/jphysiol.1975.sp010951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DeFeudis F. V. Amino acids as central neurotransmitters. Annu Rev Pharmacol. 1975;15:105–130. doi: 10.1146/annurev.pa.15.040175.000541. [DOI] [PubMed] [Google Scholar]
  7. Douglas W. W. Stimulus-secretion coupling: the concept and clues from chromaffin and other cells. Br J Pharmacol. 1968 Nov;34(3):451–474. doi: 10.1111/j.1476-5381.1968.tb08474.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Foreman J. C., Mongar J. L., Gomperts B. D. Calcium ionophores and movement of calcium ions following the physiological stimulus to a secretory process. Nature. 1973 Oct 5;245(5423):249–251. doi: 10.1038/245249a0. [DOI] [PubMed] [Google Scholar]
  9. GRAY E. G., WHITTAKER V. P. The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat. 1962 Jan;96:79–88. [PMC free article] [PubMed] [Google Scholar]
  10. Garcia A. G., Kirpekar S. M., Prat J. C. A calcium ionophore stimulating the secretion of catecholamines from the cat adrenal. J Physiol. 1975 Jan;244(1):253–262. doi: 10.1113/jphysiol.1975.sp010795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Goddard G. A., Robinson J. D. Uptake and release of calcium by rat brain synaptosomes. Brain Res. 1976 Jul 9;110(2):331–350. doi: 10.1016/0006-8993(76)90406-6. [DOI] [PubMed] [Google Scholar]
  12. Gottesfeld Z., Elliott K. A. Factors that affect the binding and uptake of gaba by brain tissue. J Neurochem. 1971 May;18(5):683–690. doi: 10.1111/j.1471-4159.1971.tb11998.x. [DOI] [PubMed] [Google Scholar]
  13. Holz R. W. The release of dopamine from synaptosomes from rat striatum by the ionophores X 537A and A 23187. Biochim Biophys Acta. 1975 Jan 14;375(1):138–152. doi: 10.1016/0005-2736(75)90079-6. [DOI] [PubMed] [Google Scholar]
  14. Iversen L. L. Catecholamine uptake processes. Br Med Bull. 1973 May;29(2):130–135. doi: 10.1093/oxfordjournals.bmb.a070982. [DOI] [PubMed] [Google Scholar]
  15. Iversen L. L., Johnston G. A. GABA uptake in rat central nervous system: comparison of uptake in slices and homogenates and the effects of some inhibitors. J Neurochem. 1971 Oct;18(10):1939–1950. doi: 10.1111/j.1471-4159.1971.tb09600.x. [DOI] [PubMed] [Google Scholar]
  16. Iversen L. L. Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol. 1971 Apr;41(4):571–591. doi: 10.1111/j.1476-5381.1971.tb07066.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kuriyama K., Weinstein H., Roberts E. Uptake of gamma-aminobutyric acid by mitochondrial and synaptosomal fractions from mouse brain. Brain Res. 1969 Dec;16(2):479–492. doi: 10.1016/0006-8993(69)90240-6. [DOI] [PubMed] [Google Scholar]
  18. Levi G., Poce U., Raiteri M. Uptake and exchange of GABA and glutamate in isolated nerve endings. Adv Exp Med Biol. 1976;69:273–289. doi: 10.1007/978-1-4684-3264-0_21. [DOI] [PubMed] [Google Scholar]
  19. Levi G., Raiteri M. Synaptosomal transport processes. Int Rev Neurobiol. 1976;19:51–74. doi: 10.1016/s0074-7742(08)60701-1. [DOI] [PubMed] [Google Scholar]
  20. Li P. P., White T. D. Rapid effects of veratridine, tetrodotoxin, gramicidin D, valinomycin and NaCN on the Na+, K+ and ATP contents of synaptosomes. J Neurochem. 1977 May;28(5):967–975. doi: 10.1111/j.1471-4159.1977.tb10658.x. [DOI] [PubMed] [Google Scholar]
  21. Martin D. L., Smith A. A., 3rd Ions and the transport of gamma-aminobutyric acid by synaptosomes. J Neurochem. 1972 Mar;19(3):841–855. doi: 10.1111/j.1471-4159.1972.tb01398.x. [DOI] [PubMed] [Google Scholar]
  22. Pressman B. C. Biological applications of ionophores. Annu Rev Biochem. 1976;45:501–530. doi: 10.1146/annurev.bi.45.070176.002441. [DOI] [PubMed] [Google Scholar]
  23. Raiteri M., Angelini F., Levi G. A simple apparatus for studying the release of neurotransmitters from synaptosomes. Eur J Pharmacol. 1974 Mar;25(3):411–414. doi: 10.1016/0014-2999(74)90272-6. [DOI] [PubMed] [Google Scholar]
  24. Raiteri M., Federico R., Coletti A., Levi G. Release and exchange studies relating to the synaptosomal uptake of GABA. J Neurochem. 1975 Jun;24(6):1243–1250. doi: 10.1111/j.1471-4159.1975.tb03905.x. [DOI] [PubMed] [Google Scholar]
  25. Raiteri M., del Carmine R., Bertollini A. Effect of desmethylimipramine on the release of (3H)norepinephrine induced by various agents in hypothalamic synaptosomes. Mol Pharmacol. 1977 Jul;13(4):746–758. [PubMed] [Google Scholar]
  26. Rubin R. P. The role of calcium in the release of neurotransmitter substances and hormones. Pharmacol Rev. 1970 Sep;22(3):389–428. [PubMed] [Google Scholar]
  27. Ryan L. D., Roskoski R., Jr Net uptake of gamma-aminobutyric acid by a high affinity synaptosomal transport system. J Pharmacol Exp Ther. 1977 Feb;200(2):285–291. [PubMed] [Google Scholar]
  28. Sellstrom A., Venema R., Henn F. Functional assessment of GABA uptake or exchange by synaptosomal fractions. Nature. 1976 Dec 16;264(5587):652–653. doi: 10.1038/264652a0. [DOI] [PubMed] [Google Scholar]
  29. Simon J. R., Martin D. L., Kroll M. Sodium-dependent efflux and exchange of GABA in synaptosomes. J Neurochem. 1974 Nov;23(5):981–991. doi: 10.1111/j.1471-4159.1974.tb10750.x. [DOI] [PubMed] [Google Scholar]
  30. Smith A. D. Cellular control of the uptake, storage and release of noradrenaline in sympathetic nerves. Biochem Soc Symp. 1972;(36):103–131. [PubMed] [Google Scholar]
  31. Stahl W. L., Swanson P. D. Uptake of calcium by subcellular fractions isolated from ouabain-treated cerebral tissues. J Neurochem. 1969 Dec;16(12):1553–1563. doi: 10.1111/j.1471-4159.1969.tb10354.x. [DOI] [PubMed] [Google Scholar]
  32. Swanson P. D., Anderson L., Stahl W. L. Uptake of calcium ions by synaptosomes from rat brain. Biochim Biophys Acta. 1974 Jul 31;356(2):174–183. doi: 10.1016/0005-2736(74)90281-8. [DOI] [PubMed] [Google Scholar]
  33. Thoa N. B., Costa J. L., Moss J., Kopin I. J. Mechanism of release of norepinephrine from peripheral adrenergic neurones by the calcium ionophores X 537A and A 23187. Life Sci. 1974 May 1;14(9):1705–1719. doi: 10.1016/0024-3205(74)90272-0. [DOI] [PubMed] [Google Scholar]
  34. WEINSTEIN H., VARON S., MUHLEMAN D. R., ROBERTS E. A CARRIER-MEDIATED TRANSFER MODEL FOR THE ACCUMULATION OF 14-C-GAMMA-AMINOBUTYRIC ACID BY SUBCELLULAR BRAIN PARTICLES. Biochem Pharmacol. 1965 Mar;14:273–288. doi: 10.1016/0006-2952(65)90192-9. [DOI] [PubMed] [Google Scholar]

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