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Metabolism of the neuromodulator d-serine

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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.

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Abbreviations

Aβ:

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)

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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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  1. Dipartimento di Biotecnologie e Scienze Molecolari, Università degli studi dell’Insubria, Varese, Italy

    Loredano Pollegioni & Silvia Sacchi

  2. Centro di Ricerca Interuniversitario in Biotecnologie Proteiche “The Protein Factory”, Politecnico di Milano and Università degli studi dell’Insubria, via J.H. Dunant 3, 21100, Varese, Italy

    Loredano Pollegioni & Silvia Sacchi

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  1. Loredano Pollegioni
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Correspondence to Loredano Pollegioni.

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Pollegioni, L., Sacchi, S. Metabolism of the neuromodulator d-serine. Cell. Mol. Life Sci. 67, 2387–2404 (2010). https://doi.org/10.1007/s00018-010-0307-9

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  • DOI: https://doi.org/10.1007/s00018-010-0307-9

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