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Journal of Biochemistry 2006 139(2):295-304; doi:10.1093/jb/mvj036
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© 2006 The Japanese Biochemical Society.

Regular Paper

Potential Role for Astroglial D-Amino Acid Oxidase in Extracellular D-Serine Metabolism and Cytotoxicity

Hwan Ki Park*, Yuji Shishido{dagger}, Sayaka Ichise-Shishido, Tomoya Kawazoe, Koji Ono, Sanae Iwana, Yumiko Tomita, Kazuko Yorita, Takashi Sakai and Kiyoshi Fukui{ddagger}

Department of Gene Regulatorics, The Institute for Enzyme Research, The University of Tokushima, Tokushima 770-8503

{ddagger} To whom correspondence should be addressed. Tel: +81-88-633-7430, Fax: +81-88-633-7431, E-mail: kiyo{at}ier.tokushima-u.ac.jp

D-Amino acid oxidase (DAO) is a flavoenzyme that catalyzes the oxidation of D-amino acids. In the brain, gene expression of DAO is detected in astrocytes. Among the possible substrates of DAO in vivo, D-serine is proposed to be a neuromodulator of the N-methyl-D-aspartate (NMDA) receptor. In a search for the physiological role of DAO in the brain, we investigated the metabolism of extracellular D-serine in glial cells. Here we show that after D-serine treatment, rat primary type-1 astrocytes exhibited increased cell death. In order to enhance the enzyme activity of DAO in cells, we established stable rat C6 glial cells overexpressing mouse DAO designated as C6/DAO. Treatment with a high dose of D-serine led to the production of hydrogen peroxide (H2O2) followed by apoptosis in C6/DAO cells. Among the amino acids tested, D-serine specifically exhibited a significant cell death–inducing effect. DAO inhibitors, i.e., sodium benzoate and chlorpromazine, partially prevented the death of C6/DAO cells treated with D-serine, indicating the involvement of DAO activity in D-serine metabolism. Overall, we consider that extracellular D-serine can gain access to intracellular DAO, being metabolized to produce H2O2. These results support the proposal that astroglial DAO plays an important role in metabolizing a neuromodulator, D-serine.

* Supported by a Japanese Government (Monbukagakusho) Scholarship.

{dagger} Present address: Brain Research Institute, Niigata University, Niigata 951-8122.


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