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J. Biol. Chem., Vol. 281, Issue 29, 20291-20302, July 21, 2006

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Modulation of D-Serine Levels via Ubiquitin-dependent Proteasomal Degradation of Serine Racemase^*

Elena Dumin, Inna Bendikov, Veronika N. Foltyn, Yoshio Misumi, Yukio Ikehara^¶, Elena Kartvelishvily, and Herman Wolosker¹

From the Department of Biochemistry, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel, Department of Cell Biology, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan, and ^¶Institute for Pharmaceutical Sciences, Daiichi University, Fukuoka 815-8511, Japang

Mammalian serine racemase is a brain-enriched enzyme that converts L- into D-serine in the nervous system. D-Serine is an endogenous co-agonist at the "glycine site" of N-methyl D-aspartate (NMDA) receptors that is required for the receptor/channel opening. Factors regulating the synthesis of D-serine have implications for the NMDA receptor transmission, but little is known on the signals and events affecting serine racemase levels. We found that serine racemase interacts with the Golgin subfamily A member 3 (Golga3) protein in yeast two-hybrid screening. The interaction was confirmed in vitro with the recombinant proteins in co-transfected HEK293 cells and in vivo by co-immunoprecipitation studies from brain homogenates. Golga3 and serine racemase co-localized at the cytosol, perinuclear Golgi region, and neuronal and glial cell processes in primary cultures. Golga3 significantly increased serine racemase steady-state levels in co-transfected HEK293 cells and primary astrocyte cultures. This observation led us to investigate mechanisms regulating serine racemase levels. We found that serine racemase is degraded through the ubiquitin-proteasomal system in a Golga3-modulated manner. Golga3 decreased the ubiquitylation of serine racemase both in vitro and in vivo and significantly increased the protein half-life in pulse-chase experiments. Our results suggest that the ubiquitin system is a main regulator of serine racemase and D-serine levels. Modulation of serine racemase degradation, such as that promoted by Golga3, provides a new mechanism for regulating brain D-serine levels and NMDA receptor activity.

Received for publication, March 1, 2006 , and in revised form, May 18, 2006.

^* This work was supported by grants from the Israel Science Foundation, Rappaport Institute for Research in the Medical Sciences, Atkins Medical Research Fund for Gerontology, and the public committee for the designation of estate funds from the Ministry of Justice (to H. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Fax: 972-4-829-5384, E-mail: hwolosker{at}tx.technion.ac.il.

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