D-Serine as a putative glial neurotransmitter.

Abundant recent evidence favors a neurotransmitter/neuromodulator role for D-serine. D-serine is synthesized from L-serine by serine racemase in astrocytic glia that ensheath synapses, especially in regions of the brain that are enriched in NMDA-glutamate receptors. D-serine is more potent than glycine at activating the 'glycine' site of these receptors. Moreover, selective degradation of D-serine but not glycine by D-amino acid oxidase markedly reduces NMDA neurotransmission. D-serine appears to be released physiologically in response to activation by glutamate of AMPA-glutamate receptors on D-serine-containing glia. This causes glutamate-receptor-interacting protein, which binds serine racemase, to stimulate enzyme activity and D-serine release. Thus, glutamate triggers the release of D-serine so that the two amino acids can act together on postsynaptic NMDA receptors. D-serine also plays a role in neural development, being released from Bergmann glia to chemokinetically enhance the migration of granule cell cerebellar neurons from the external to the internal granular layer.

[1]  S. Snyder,et al.  d-Serine as a Neuromodulator: Regional and Developmental Localizations in Rat Brain Glia Resemble NMDA Receptors , 1997, The Journal of Neuroscience.

[2]  S. Snyder,et al.  Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Nishikawa,et al.  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. , 1992, Journal of chromatography.

[4]  Santiago Lamas,et al.  Nitrosylation The Prototypic Redox-Based Signaling Mechanism , 2001, Cell.

[5]  Chi-Ying F. Huang,et al.  PICK1, an Anchoring Protein That Specifically Targets Protein Kinase Cα to Mitochondria Selectively upon Serum Stimulation in NIH 3T3 Cells* , 2003, Journal of Biological Chemistry.

[6]  K N Sheth,et al.  Purification of serine racemase: biosynthesis of the neuromodulator D-serine. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Sachio Takashima,et al.  Embryonic Development and Postnatal Changes in Free d‐Aspartate and d‐Serine in the Human Prefrontal Cortex , 1993, Journal of neurochemistry.

[8]  S. R. Wickramasinghe,et al.  Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[10]  S H Snyder,et al.  Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  R. Huganir,et al.  Molecular mechanisms of glutamate receptor clustering at excitatory synapses , 1998, Current Opinion in Neurobiology.

[12]  T. Nishikawa,et al.  Extracellular concentration of endogenous free d-serine in the rat brain as revealed by in vivo microdialysis , 1995, Neuroscience.

[13]  T. Nishikawa,et al.  Endogenous d‐Serine in Rat Brain: N‐Methyl‐d‐Aspartate Receptor‐Related Distribution and Aging , 1993, Journal of neurochemistry.

[14]  Loredano Pollegioni,et al.  Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  P. Ascher,et al.  Glycine potentiates the NMDA response in cultured mouse brain neurons , 1987, Nature.

[16]  A. Neidle,et al.  The origin and turnover of D-serine in brain. , 1997, Biochemical and biophysical research communications.

[17]  J. Kemp,et al.  NMDA receptor pathways as drug targets , 2002, Nature Neuroscience.

[18]  A. Lajtha,et al.  The presence of free D-aspartic acid in rodents and man. , 1986, Biochemical and biophysical research communications.

[19]  S. Snyder,et al.  Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[20]  H. Krebs Metabolism of amino-acids: Deamination of amino-acids. , 1935, The Biochemical journal.

[21]  S. Shimizu,et al.  Occurrence of pyridoxal 5'-phosphate-dependent serine racemase in silkworm, Bombyx mori. , 1998, Biochemical and biophysical research communications.

[22]  R. Panizzutti,et al.  Glial transport of the neuromodulator d-serine , 2002, Brain Research.

[23]  I. Galve-Roperh,et al.  Direct Calcium Binding Results in Activation of Brain Serine Racemase* , 2002, The Journal of Biological Chemistry.

[24]  J. Coyle,et al.  The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. , 2001, The American journal of psychiatry.

[25]  V. Gundersen,et al.  Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate , 2004, Nature Neuroscience.

[26]  K. Harada,et al.  The presence of free D‐serine in rat brain , 1992, FEBS letters.

[27]  Nicholas Lange,et al.  D-serine added to antipsychotics for the treatment of schizophrenia , 1998, Biological Psychiatry.

[28]  D. Linden,et al.  D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Tomomi Kobayashi,et al.  Distribution and MK-801-induced expression of serine racemase mRNA in rat brain by real-time quantitative PCR. , 2004, Brain research. Molecular brain research.

[30]  S. Snyder,et al.  D-aspartate localizations imply neuronal and neuroendocrine roles. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Poo,et al.  Contribution of astrocytes to hippocampal long-term potentiation through release of d-serine , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  P. Rakic,et al.  Modulation of neuronal migration by NMDA receptors. , 1993, Science.

[33]  R. Huganir,et al.  Requirement of AMPA Receptor GluR2 Phosphorylation for Cerebellar Long-Term Depression , 2003, Science.

[34]  R. Panizzutti,et al.  Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity* , 2005, Journal of Biological Chemistry.

[35]  G M Shepherd,et al.  Glycine exerts potent inhibitory actions on mammalian olfactory bulb neurons. , 1994, Journal of neurophysiology.

[36]  M. Yamazaki,et al.  Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs , 1992, Nature.

[37]  S. Barger,et al.  Induction of serine racemase expression and D-serine release from microglia by amyloid β-peptide , 2004, Journal of Neuroinflammation.

[38]  S. Snyder,et al.  Heme Oxygenase-2 Is Activated by Calcium-Calmodulin* , 2004, Journal of Biological Chemistry.

[39]  S. Snyder,et al.  D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. Panizzutti,et al.  Cofactors of serine racemase that physiologically stimulate the synthesis of the N-methyl-d-aspartate (NMDA) receptor coagonist d-serine , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[41]  P. Wood The co-agonist concept: is the NMDA-associated glycine receptor saturated in vivo? , 1995, Life sciences.

[42]  T. Nishikawa,et al.  Free d-serine, d-aspartate and d-alanine in central nervous system and serum in mutant mice lacking d-amino acid oxidase , 1993, Neuroscience Letters.

[43]  A. Hashimoto,et al.  Free d-aspartate and d-serine in the mammalian brain and periphery , 1997, Progress in Neurobiology.