Advertisement

Neurochemical Research

, Volume 18, Issue 4, pp 365–376 | Cite as

GABA—The quintessential neurotransmitter: Electroneutrality, fidelity, specificity, and a model for the ligand binding site of GABAA receptors

  • Eugene Roberts
  • Mark A. Sherman
Microanatomy and Metabolism

Abstract

Alone of the known neurotransmitters, GABA is an electroneutral zwitterion (pI=7.3) at physiological pH. This confers the highest probability of successfully traversing densely packed synaptic gaps without interacting electrostatically with charged entities enroute, making GABA a high fidelity neurotransmitter. Inhibitory tone in the nervous system is coordinately coupled with physiological activity by means of the GABA system, acidification increasing GABA formation and its Cl channel-opening efficacy, while decreasing its removal by transport and metabolic degradation. The above, together with diminution upon acidification of the postsynaptic efficacy of glutamate on excitatory NMDA receptors constitutes a sensitively responsive mechanism by which protons control levels of neural activity, locally and globally. A model made of the GABA binding site of GABAA receptors based on H-bond and hydrophobic interactions makes it seem unlikely that any other substance known to occur in nerve tissue would give rise to a high noise level at GABAA receptors.

Key Words

GABA electroneutrality information transmittal fidelity GABAergic function proton enhancement GABAA receptor cavity model 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    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.Google Scholar
  2. 2.
    Roberts, E. 1976. Disinhibition of an organizing principle in the nervous system—The role of the GABA system. Application to neurologic and psychiatric disorders. Pages 515–539, in Roberts, E., Chase, T. N., and Tower, D. B. (eds.), GABA in Nervous System Function, Kroc Foundation Series, Vol. 5, Raven Press, New York.Google Scholar
  3. 3.
    Roberts, E. 1986. GABA: The road to neurotransmitter status. Pages 1–39,in Olsen, R.W. and Venter, J.C. (eds.), Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties, Alan R. Liss, Inc., New York.Google Scholar
  4. 4.
    Roberts, E. 1986. Failure of GABAergic inhibition: A key to local and global seizures. Adv. Neurol. 44:319–341.Google Scholar
  5. 5.
    Roberts, E. 1986. What do GABA neurons really do? They make possible variability generation in relation to demand. Exp. Neurol. 93:279–290.Google Scholar
  6. 6.
    Barker, J. L., and Mathers, D. A. 1981. GABA analogues activate channels of different duration on cultured mouse spinal neurons. Science 212:358–361.Google Scholar
  7. 7.
    Olsen, R. W., and Tobin, A. J. 1990. Molecular biology of GABAA receptors. FASEB J 4:1469–1480.Google Scholar
  8. 8.
    Wisden, W., Laurie, D. J., Monyer, H., and Seeburg, P. H. 1992. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J. Neurosci. 12:1040–1062.Google Scholar
  9. 9.
    Laurie, D. J., Seeburg, P. H., and Wisden, W. 1992. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J. Neurosci. 12:1063–1076.Google Scholar
  10. 10.
    Burt, D. R., and Kamatchi, G. L. 1991. GABAA receptor subtypes: from pharmacology to molecular biology. FASEB J 5:2916–2923.Google Scholar
  11. 11.
    Greenstein, J. P., and Winitz, M. 1961. Chemistry of the Amino Acids. Vol. 1, pp. 486–489. John Wiley & Sons, Inc., New York, London.Google Scholar
  12. 12.
    Vos, J., Kuriyama, K., and Roberts, E. 1968. Electrophoretic mobilities of brain subcellular particles and binding of γ-aminobutyric acid, acetylcholine, norepinephrine, and 5-hydroxytryptamine. Brain Res. 9:224–230.Google Scholar
  13. 13.
    Sakmann, B. 1992. Elementary steps in synaptic transmission revealed by currents through single ion channels. Neuron 8:613–629.Google Scholar
  14. 14.
    Bormann, J., Hamill, O. P., and Sakmann, B. 1987. Mechanism of anion permeation through channels gated by glycine and γ-aminobutyric acid in mouse cultured spinal neurones. J. Physiol. 385:243–286.Google Scholar
  15. 15.
    Traynelis, S. F., and Cull-Candy, S. G. 1990. Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons. Nature 345:347–350.Google Scholar
  16. 16.
    Grinstein, S., and Rothstein, A. 1986. Mechanisms of regulation of the Na+/H+ exchanger. J. Membrane Biol. 90:1–12.Google Scholar
  17. 17.
    Moolenaar, W. H. 1986. Effects of growth factors on intracellular pH regulation. Ann. Rev. Physiol. 48:363–376.Google Scholar
  18. 18.
    Roberts, E., and Eidelberg, E. 1960. Metabolic and neurophysiological roles of γ-aminobutyric acid. Int. Rev. Neurobiol. 2:279–332.Google Scholar
  19. 19.
    Woodbury, D. M. 1980. Antiepileptic drugs: carbonic anhydrase inhibitors. Pages 617–633, in Glaser, G. H., Penry, J. K., and Woodbury, D. M. (eds.), Antiepileptic Drugs: Mechanisms of Action, Raven Press, New York.Google Scholar
  20. 20.
    White, H. S., Woodbury, D. M., Chen, C. F., Kemp, J. W., Chow, S. Y., and Yen-Chow, Y. C. 1986. Role of glial cation and anion transport mechanisms in etiology and arrest of seizures. Adv. Neurol. 44:695–712.Google Scholar
  21. 21.
    Schlue, W.-R., and Deitmer, J. W. 1988. Ionic mechanisms of intracellular pH regulation in the nervous system. Ciba Fdn. Symp. 139:47–69.Google Scholar
  22. 22.
    Erlander, M. G., and Tobin, A. J. 1991. The structural and functional heterogeneity of glutamic acid decarboxylase. A review. Neurochem. Res. 16:215–226.Google Scholar
  23. 23.
    Wu, J.-Y., Matsuda, T., and Roberts, E. 1973. Purification and characterization of glutamate decarboxylase from mouse brain. J. Biol. Chem. 248:3029–3034.Google Scholar
  24. 24.
    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.Google Scholar
  25. 25.
    Sano, K., and Roberts, E. 1963. Binding of γ-aminobutyric acid by mouse brain preparations. Biochem. Pharmacol. 12:489–502.Google Scholar
  26. 26.
    Roberts, E., Liron, Z., Wong, E., and Schroeder, F. 1985. Roles of proton removal and membrane fluidity in Na+- and Cl-dependent uptake of γ-aminobutyric acid by mouse brain particles. Exp. Neurol. 88:13–26.Google Scholar
  27. 27.
    Liron, Z., Wong, E., and Roberts, E. 1988. Studies on uptake of γ-aminobutyric acid by mouse brain particles; toward the development of a model. Brain Res. 444:119–132.Google Scholar
  28. 28.
    Takeuchi, A., and Takeuchi, N. 1967. Anion permeability of the inhibitory post-synaptic membrane of the crayfish neuromuscular junction. J. Physiol. 191:575–590.Google Scholar
  29. 29.
    Perutz, M.F. 1978. Hemoglobin structure and respiratory transport. Sci. Am. 239:92–125.Google Scholar
  30. 30.
    Martinez-Carrion, M. 1967. Evidence of a critical histidine residue in soluble aspartic aminotransferase. J. Biol. Chem. 242:1426–1430.Google Scholar
  31. 31.
    Westhead, E. W. 1965. Photooxidation with rose bengal of a critical histidine residue in yeast enolase. Biochemistry 4:2139–2144.Google Scholar
  32. 32.
    Melchior, Jr., W. B., and Fahrney, D. 1970. Ethoxyformylation of proteins. Reaction of ethoxyformic anhydride with α-chymotrypsin, pepsin, and pancreatic ribonuclease at pH 4. Biochemistry 9:251–258.Google Scholar
  33. 33.
    Volwerk, J. J., Pieterson, W. A., and de Haas, G. H. 1974. Histidine at the active site of phospholipase A2. Biochemistry 13:1446–1454.Google Scholar
  34. 34.
    Martinez-Carrion, M., Kuczenski, R., Tiemeier, D. C., and Peterson, D. L. 1970. The structure and enzyme-coenzyme relationship of supernatant aspartate transaminase after dye sensitized photooxidation. J. Biol. Chem. 245:799–805.Google Scholar
  35. 35.
    Harmsen, B. J. M., De Bruin, S. H., Janssen, L. H. M., Rodrigues De Miranada, J. F., and Van Os, G. A. J. 1971. pK change of imidazole groups in bovine serum albumin due to the conformational change at neutral pH. Biochemistry 10:3217–3221.Google Scholar
  36. 36.
    Padan, E., Sarkar, H. K., Viitanen, P. V., Poonian, M. S., and Kaback, H. R. 1985. Site-specific mutagenesis of histidine residues in the lac permease ofEscherichia coli. Proc. Natl. Acad. Sci. USA 82:6765–6768.Google Scholar
  37. 37.
    Wieland, H. A., Luddens, H., and Seeburg, P. H. 1992. A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J. Biol. Chem. 267:1426–1429.Google Scholar
  38. 38.
    Smart, T. G., Moss, S. J., Xie, X., and Huganir, R. L. 1991. GABAA receptors are differentially sensitive to zinc: dependence on subunit composition. Br. J. Pharmacol. 103:1837–1839.Google Scholar
  39. 39.
    Draguhn, A., Verdorn, T. A., Ewert, M., Seeburg, P. H., and Sakmann, B. 1990. Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+. Neuron 5:781–788.Google Scholar
  40. 40.
    Quiocho, F. A. 1990. Atomic structures of periplasmic binding proteins and the high-affinity active transport systems in bacteria. Phil. Trans. R. Soc. Lond. B 326:341–351.Google Scholar
  41. 41.
    Krause, D. N., Ikeda, K., and Roberts, E. 1981. Dose-conductance relationships for GABA agonists and the effect of uptake inhibitors in crayfish stretch receptor neurons. Brain Res. 225:319–332.Google Scholar
  42. 42.
    Roberts, E., Krause, D. N., Wong, E., and Mori, A. 1981. Different efficacies of d- and l-γ-amino-β-hydroxybutyric acids in GABA receptor and transport test systems. J. Neurosci. 1:132–140.Google Scholar
  43. 43.
    Pooler, G. W., and Steward, E. G. 1987. Structural comparisons between GABA, bicuculline and semi-rigid GABA analogues. J. Mol. Struct. 156:247–253.Google Scholar
  44. 44.
    Lipkowitz, K. B., Gilardi, R.D. and Aprison, M. H. 1989. Electronic and structural features of gamma-aminobutyric acid (GABA) and four of its direct agonists. J. Mol. Struct. 195:65–77.Google Scholar
  45. 45.
    Lee, F. S., Chu, Z.-T., Bolger, M. B., and Warshel, A. 1992. Calculations of antibody-antigen interactions: microscopic and semimicroscopic evaluation of the free energies of binding of phosphorylcholine analogs to McPC603. Protein Engineering 5:215–228.Google Scholar
  46. 46.
    Squires, R. F. and Saederup, E. A review of evidence for GABAergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of “functional” psychosis. Neurochem. Res. 16:1099–1111.Google Scholar
  47. 47.
    Mayo, S. L., Olafson, B.D., and Goddard III, W. A. 1990. Dreiding: A generic force field for molecular simulations. J. Phys. Chem. 94:8897–8909.Google Scholar

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Eugene Roberts
    • 1
  • Mark A. Sherman
    • 2
  1. 1.Department of NeurobiochemistryBeckman Research Institute of the City of HopeDuarte
  2. 2.Department of BiologyBeckman Research Institute of the City of HopeDuarte

Personalised recommendations