Study on the mechanism of neural D-serine metabolism and application for the pharmacotherapeutics of schizophrenia

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Regulation of NMDA receptor function by the modulation of endogenous D-serine in the central nervous system has been considered to be one of the crucial target pathways for the development of novel treatment of antipsychotics-resistant schizophrenia. In this study, we have been characterized molecular mechanisms that regulate D-serine metabolism in the mammalian brain. In first, using Xenopus oocyte expression cloning system, we have isolated D-serine modulator-1 (dsm-1), which regulates uptake and release of extracellular D-serine in the brain. Characterization of biochemical kinetics and distribution of dsm-1 suggested the dsm-2 gene product can be one of the molecular targets for the drug-screening of novel antipsychotics. In second, by differential screening, we have isolated D-serine responsive transcript-2 (dsr-2). The distribution of dsr-2 was closely related to endogenous D-serine and NMDA receptor NR2B subtype in the central nervous system. Genomic structure and the developmentally regulated localization of dsr-2 together suggested that dsr-2 gene product is involved in the D-serine metabolism and function. These findings and further study should provide us an insight to understand the mechanism of D-serine metabolism in the brain and possible molecular targets for the development of antischizophrenic drugs.