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Cellular and Molecular Life Sciences

, Volume 67, Issue 14, pp 2387–2404 | Cite as

Metabolism of the neuromodulator d-serine

  • Loredano Pollegioni
  • Silvia Sacchi
Review

Abstract

Over the past years, accumulating evidence has indicated that d-serine is the endogenous ligand for the glycine-modulatory binding site on the NR1 subunit of N-methyl-d-aspartate receptors in various brain areas. d-Serine is synthesized in glial cells and neurons by the pyridoxal-5′ phosphate-dependent enzyme serine racemase, and it is released upon activation of glutamate receptors. The cellular concentration of this novel messenger is regulated by both serine racemase isomerization and elimination reactions, as well as by its selective degradation catalyzed by the flavin adenine dinucleotide-containing flavoenzyme d-amino acid oxidase. Here, we present an overview of the current knowledge of the metabolism of d-serine in human brain at the molecular and cellular levels, with a specific emphasis on the brain localization and regulatory pathways of d-serine, serine racemase, and d-amino acid oxidase. Furthermore, we discuss how d-serine is involved with specific pathological conditions related to N-methyl-d-aspartate receptors over- or down-regulation.

Keywords

d-Serine Gliotransmitter Serine racemase d-Amino acid oxidase Neurotransmission NMDA receptors 

Abbreviations

Amyloid β-peptide

AD

Alzheimer’s disease

AMPA

α-Amino-3-hydroxy-5-methylisooxazole-4-propionic acid

CNS

Central nervous system

CP

Choroid plexus

CSF

Cerebrospinal fluid

DAAO

d-Amino acid oxidase (EC 1.4.3.3)

d-DOPA

d-3,4-Dihydroxyphenylalanine

DPFC

Dorsolateral prefrontal cortex

FAD

Flavin adenine dinucleotide

Golga3

Golgin subfamily A member

GRIP

Glutamate receptor interacting protein

PDZ

PSD95/disc large/ZO-1

PICK1

Protein interacting with C kinase 1

PIP2

Phosphatidylinositol(4,5)biphosphate

PLP

Pyridoxal-5′ phosphate

NMDAR

N-methyl-d-aspartate receptor

NO

Nitric oxide

SR

Serine racemase (EC 5.1.1.18)

Notes

Acknowledgments

This work was supported by grants from Fondo di Ateneo per la Ricerca to L. Pollegioni and S. Sacchi, and from Fondazione CARIPLO to L. Pollegioni. We are grateful for the support of Consorzio Interuniversitario per le Biotecnologie and the Centro di Ricerca in Biotecnologie per la Salute Umana (Università degli studi dell’Insubria). The authors are grateful to all members of their laboratory and particularly to Mirella Pilone, Gianluca Molla (even for help in preparing Fig. 3), Laura Caldinelli, and Pamela Cappelletti for helpful discussions.

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© Springer Basel AG 2010

Authors and Affiliations

  1. 1.Dipartimento di Biotecnologie e Scienze MolecolariUniversità degli studi dell’InsubriaVareseItaly
  2. 2.Centro di Ricerca Interuniversitario in Biotecnologie Proteiche “The Protein Factory”Politecnico di Milano and Università degli studi dell’InsubriaVareseItaly

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