Skip to main content
Log in

D-Amino Acids as Putative Neurotransmitters: Focus on D-Serine

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Of the twenty amino acids in the mammalian body, only serine and aspartate occur in D-configuration as well as L-configuration in significant amount. D-serine is selectively concentrated in the brain, localized to protoplasmic astrocytes that ensheath synapses and distributed similarly to N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. D-serine has been found to function as an endogenous ligand for the “glycine” site of the NMDA receptor. Evidences for this include the greater potency of D-serine to activate this site than glycine, and D-amino acid oxidase, which degrades D-serine as well as other neutral D-amino acids, markedly attenuates NMDA neurotransmission. D-serine is also formed by serine racemase, a recently cloned enzyme that converts L-serine to D-serine. Thus, in many ways D-serine fulfills criteria for defining its functionality as a neurotransmitter and challenges the dogma relating to neurotransmission, for it is the “unnatural” isomeric form of an amino acid derived from glia rather than neurons.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Dunlop, D. S., Neidle, A., McHale, D., Dunlop, D. M., and Lajtha, A. 1986. The presence of free D-aspartic acid in rodents and man. Biochem. Biophys. Res. Commun. 141:27-32.

    Google Scholar 

  2. Hashimoto, A., Nishikawa, T., Oka, T., Takahashi, K. and Hayashi, T. 1992. Determination of free amino acid enantiomers in rat brain and serum by high-performance liquid chromatography after derivatization with N-tert.-butyloxycarbonyl-L-cysteine and o-phthaldialdehyde. J. Chromatogr. 582:41-8.

    Google Scholar 

  3. Hashimoto, A., Nishikawa, T., Hayashi, T., Fujii, N., Harada, K., Oka, T. and Takahashi, K. 1992. The presence of free D-serine in rat brain. FEBS Lett. 296:33-36.

    Google Scholar 

  4. Hashimoto, A. and Oka, T. 1997. Free D-aspartate and Dserine in the mammalian brain and periphery. Prog. Neurobiol. 52:325-53.

    Google Scholar 

  5. Hashimoto, A., Nishikawa, T., Oka, T. and Takahashi, K. 1993. Endogenous D-serine in rat brain: N-methyl-D-aspartate receptor-related distribution and aging. J. Neurochem. 60:783-6.

    Google Scholar 

  6. Matsui, T., Sekiguchi, M., Hashimoto, A., Tomita, U., Nishikawa, T. and Wada, K. 1995. Functional comparison of D-serine and glycine in rodents: the effect on cloned NMDA receptors and the extracellular concentration. J. Neurochem. 65: 454-8.

    Google Scholar 

  7. Schell, M. J., Molliver, M. E. and Snyder, S. H. 1995. D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc. Natl. Acad. Sci. USA. 92:3948-52.

    Google Scholar 

  8. Krebs, H. A. 1935. CXCVII. Metabolism of amino acids. III. Deamination of amino acids. Biochem. J. 29:1620-1644.

    Google Scholar 

  9. Horiike, K., Tojo, H., Arai, R., Nozaki, M. and Maeda, T. 1994. D-amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes. Brain Res. 652:297-303.

    Google Scholar 

  10. Hashimoto, A., Nishikawa, T., Konno, R., Niwa, A., Yasumura, Y., Oka, T. and Takahashi, K. 1993. Free D-serine, D-aspartate and D-alanine in central nervous system and serum in mutant mice lacking D-amino acid oxidase. Neurosci. Lett. 152:33-6.

    Google Scholar 

  11. Levison, S. W. and McCarthy, K. D. 1991. Culturing Nerve Cells. Pages 309-336 in Banner, G. K. and Goslin K. (eds), MIT Press, Cambridge.

    Google Scholar 

  12. Schell, M. J., Brady, R. O., Jr., Molliver, M. E. and Snyder, S. H. 1997. D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J. Neurosci. 17:1604-15.

    Google Scholar 

  13. Trombley, P. Q. and Shepherd, G. M. 1994. Glycine exerts potent inhibitory actions on mammalian olfactory bulb neurons. J. Neurophysiol. 71:761-7.

    Google Scholar 

  14. Hashimoto, A., Oka, T. and Nishikawa, T. 1995. Anatomical distribution and postnatal changes in endogenous free D-aspartate and D-serine in rat brain and periphery. Eur. J. Neurosci. 7: 1657-63.

    Google Scholar 

  15. Rossi, D. J. and Slater, N. T. 1993. The developmental onset of NMDA receptor-channel activity during neuronal migration. Neuropharmacology. 32:1239-48.

    Google Scholar 

  16. Komuro, H. and Rakic, P. 1993. Modulation of neuronal migration by NMDA receptors. Science. 260:95-7.

    Google Scholar 

  17. Garthwaite, J. and Brodbelt, A. R. 1989. Synaptic activation of N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors in the mossy fibre pathway in adult and immature rat cerebellar slices. Neuroscience. 29:401-12.

    Google Scholar 

  18. Dunlop, D. S. and Neidle, A. 1997. The origin and turnover of D-serine in brain. Biochem. Biophys. Res. Commun. 235:26-30.

    Google Scholar 

  19. Uo, T., Yoshimura, T., Shimizu, S. and Esaki, N. 1998. Occurrence of pyridoxal 5'-phosphate-dependent serine racemase in silkworm, Bombyx mori. Biochem. Biophys. Res. Commun. 246:31-4.

    Google Scholar 

  20. Wolosker, H., Sheth, K. N., Takahashi, M., Mothet, J. P., Brady, R. O., Jr., Ferris, C. D. and Snyder, S. H. 1999. Purification of serine racemase: biosynthesis of the neuromodulator D-serine. Proc. Natl. Acad. Sci. U S A. 96:721-5.

    Google Scholar 

  21. Wolosker, H., Blackshaw, S., and Snyder, S. H. 1999. Serine racemase: A glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc. Natl. Acad. Sci. U S A. 96:13409-14.

    Google Scholar 

  22. Denu, J. M. and Fitzpatrick, P. F. 1994. pH and kinetic isotope effects on the oxidative half-reaction of D-amino-acid oxidase. J. Biol. Chem. 269:15054-9.

    Google Scholar 

  23. D'Aniello, A., Vetere, A. and Petrucelli, L. 1993. Further study on the specificity of D-amino acid oxidase and D-aspartate oxidase and time course for complete oxidation of D-amino acids. Comp. Biochem. Physiol. [B]. 105:731-4.

    Google Scholar 

  24. Mothet, J. P., Parent, A. T., Wolosker, H., Brady Jr., R. O., Linden, D. J., Ferris, C. D., Rogawski, M. A. and Snyder, S. H. 2000. D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. USA. 97:4926-4931, 2000.

    Google Scholar 

  25. Mothet, J. P., Brady, R. O., Wolosker, H., Molliver, M. E. and Snyder, S. H. 1998. Physiological relevance of endogenous Dserine in the activation of NMDA receptors in the cerebellum of young rats. Soc. Neurosci. 24:332.

    Google Scholar 

  26. Bredt, D. S. and Snyder, S. H. 1989. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc. Natl. Acad. Sci. USA. 86:9030-3.

    Google Scholar 

  27. Berger, A. J., Dieudonne, S. and Ascher, P. 1998. Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J. Neurophysiol. 80:3336-40.

    Google Scholar 

  28. Hashimoto, A., Oka, T. and Nishikawa, T. 1995. Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo microdialysis. Neuroscience. 66:635-43.

    Google Scholar 

  29. Hashimoto, A., Kumashiro, S., Nizhikawa, T., Oka, T., Takahashi, K., Mito, T., Takashima, S., Doi, N., Mizutani, Y., Yamazaki, T. and et al. 1993. Embryonic development and postnatal changes in free D-aspartate and D-serine in the human prefrontal cortex. J. Neurochem. 61:348-51.

    Google Scholar 

  30. Schell, M. J., Cooper, O. B. and Snyder, S. H. 1997. D-aspartate localizations imply neuronal and neuroendocrine roles. Proc. Natl. Acad. Sci. USA. 94:2013-8.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Snyder, S.H., Kim, P.M. D-Amino Acids as Putative Neurotransmitters: Focus on D-Serine. Neurochem Res 25, 553–560 (2000). https://doi.org/10.1023/A:1007586314648

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007586314648

Navigation