D-Serine metabolism in C6 glioma cells: Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO).
D-Serine metabolism in C6 glioma cells: Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO).
复制标题
DOI：
10.1002/jnr.22332
复制
发表时间：
2010-06
影响因子：
4.2
通讯作者：
Burnet, Philip W. J.
中科院分区：
文献类型：
--
作者：
Sikka, Pilleriin;Walker, Rosie;Cockayne, Rebecca;Wood, Matthew J. A.;Harrison, Paul J.;Burnet, Philip W. J.
D-丝氨酸是一种内源性N-甲基-D-天冬氨酸(NMDA)受体共激动剂。它是由L-丝氨酸通过丝氨酸消旋酶合成的，但其代谢的许多方面尚不清楚，特别是在缺乏D-丝氨酸主要降解酶活性的D-氨基酸氧化酶(DAO)的前脑。可能的机制包括在α，β-消除酶模式下工作的SRR(将D-丝氨酸转化为丙酮酸)和丝氨酸转运的调节，其中涉及丙氨酸-丝氨酸-半胱氨酸转运体ASCT2。在这里，我们报道了对C6胶质瘤细胞的研究，这种细胞“模拟”前脑，因为这些细胞表达SRR和ASCT2，但缺乏DAO活性。我们检测了D-丝氨酸、ASCT2、SRR和DAO在两种情况下的表达和DAO活性：细胞与丝氨酸异构体孵育48小时后，分别通过转染法和RNA干扰法增加或降低SRR的表达。与丝氨酸对映体孵育可降低[~3H]D-丝氨酸摄取和ASCT2 mRNA，增加SRR免疫反应性，但不改变DAO免疫反应性，DAO活性仍未被检测到。SRR过表达增加D-丝氨酸和丙酮酸，降低[~3H]D-丝氨酸摄取和ASCT2 mRNA，但不影响DAO。SRR基因敲除没有改变任何参数。我们的数据表明，当DAO活性缺失时，ASCT2介导的D-丝氨酸转运对D-丝氨酸稳态有显著贡献。调节D-丝氨酸的因素对于了解正常的NMDA受体功能很重要，因为D-丝氨酸与DAO和SRR一起参与了精神分裂症的发病和治疗。©2010 Wiley-Liss公司。
D-serine is an endogenous N-methyl-D-aspartate (NMDA) receptor coagonist. It is synthesized from L-serine by serine racemase (SRR), but many aspects of its metabolism remain unclear, especially in the forebrain, which lacks active D-amino acid oxidase (DAO), the major D-serine degradative enzyme. Candidate mechanisms include SRR operating in α,β-eliminase mode (converting D-serine to pyruvate) and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated. Here we report studies in C6 glioma cells, which “simulate” the forebrain, in that the cells express SRR and ASCT2 but lack DAO activity. We measured D-serine, ASCT2, SRR, and DAO expression and DAO activity in two situations: after incubation of cells for 48 hr with serine isomers and after increased or decreased SRR expression by transfection and RNA interference, respectively. Incubation with serine enantiomers decreased [3H]D-serine uptake and ASCT2 mRNA and increased SRR immunoreactivity but did not alter DAO immunoreactivity, and DAO activity remained undetectable. SRR overexpression increased D-serine and pyruvate and decreased [3H]D-serine uptake and ASCT2 mRNA but did not affect DAO. SRR knockdown did not alter any of the parameters. Our data suggest that D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent. The factors regulating D-serine are important for understanding normal NMDA receptor function and because D-serine, along with DAO and SRR, is implicated in the pathogenesis and treatment of schizophrenia. © 2010 Wiley-Liss, Inc.
登录
查看更多内容
影响因子：
4.8
作者：
Kartvelishvily, Elena;Shleper, Maria;Wolosker, Herman
通讯作者：
Wolosker, Herman
影响因子：
7.6
作者：
Duffy, Steven;Labrie, Viviane;Roder, John C.
通讯作者：
Roder, John C.
影响因子：
4.8
作者：
Dumin, Elena;Bendikov, Inna;Wolosker, Herman
通讯作者：
Wolosker, Herman
影响因子：
6.2
作者：
Martineau, Magalie;Galli, Thierry;Mothet, Jean-Pierre
通讯作者：
Mothet, Jean-Pierre
影响因子：
2.5
作者：
Miya, Kazushi;Inoue, Ran;Mori, Hisashi
通讯作者：
Mori, Hisashi