A novel Na+-Independent alanine-serine-cysteine transporter 1 inhibitor inhibits both influx and efflux of D-Serine

详细信息    查看全文

• 作者：Katsuya Sakimura ; Kenji Nakao ; Masato Yoshikawa ; Motohisa Suzuki and Haruhide Kimura
• 刊名：Journal of Neuroscience Research
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：94
• 期：10
• 页码：888-895
• 全文大小：306K
• ISSN：1097-4547

文摘

NMDA receptor dysfunctions are hypothesized to underlie the pathophysiology of schizophrenia, and treatment with D-serine (D-Ser), an NMDA receptor coagonist, may improve the clinical symptoms of schizophrenia. Thus, upregulating the synaptic D-Ser level is a novel strategy for schizophrenia treatment. Na⁺-independent alanine-serine-cysteine transporter 1 (asc-1) is a transporter responsible for regulating the extracellular D-Ser levels in the brain. In this study, we discovered a novel asc-1 inhibitor, (+)-amino(1-(3,5-dichlorophenyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (ACPP), and assessed its pharmacological profile. ACPP inhibited the D-[³H]Ser uptake in human asc-1-expressing CHO cells and rat primary neurons with IC₅₀ values of 0.72 ± 0.13 and 0.89 ± 0.30 μM, respectively. In accordance with the lower asc-1 expression levels in astrocytes, ACPP did not inhibit D-Ser uptake in rat primary astrocytes. In a microdialysis study, ACPP dose dependently decreased the extracellular D-Ser levels in the rat hippocampus under the same conditions in which the asc-1 inhibitor S-methyl-L-cysteine (SMLC) increased it. To obtain insights into this difference, we conducted a D-[³H]Ser efflux assay using asc-1-expressing CHO cells. ACPP inhibited D-[³H]Ser efflux, whereas SMLC increased it. These results suggest that ACPP is a novel inhibitor of asc-1.