Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain*
Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain*
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DOI：
10.1074/jbc.m110.187443
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发表时间：
2010-10
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通讯作者：
J. Yang;A. Wada;Kazuyuki Yoshida;Yurika Miyoshi;T. Sayano;Kayoko Esaki;Masami O. Kinoshita;Shozo Tomonaga;N. Azuma;Masahiko Watanabe;K. Hamase;K. Zaitsu;T. Machida;A. Messing;S. Itohara;Y. Hirabayashi;S. Furuya
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作者：
J. Yang;A. Wada;Kazuyuki Yoshida;Yurika Miyoshi;T. Sayano;Kayoko Esaki;Masami O. Kinoshita;Shozo Tomonaga;N. Azuma;Masahiko Watanabe;K. Hamase;K. Zaitsu;T. Machida;A. Messing;S. Itohara;Y. Hirabayashi;S. Furuya
在哺乳动物的大脑中，d-丝氨酸是由l-丝氨酸通过丝氨酸消旋酶合成的，它在n -甲基-d-天冬氨酸（NMDA）选择性谷氨酸受体的甘氨酸调节位点作为一种强制性的协同激动剂。虽然d-丝氨酸水平的降低与NMDA受体功能低下有关，这被认为发生在精神分裂症中，但前体l-丝氨酸的来源及其在成人大脑中d-丝氨酸代谢中的作用尚未确定。我们通过产生条件缺失d-3-磷酸甘油脱氢酶（Phgdh; EC 1.1.1.95）的小鼠，研究了脑内通过磷酸化途径合成的l-丝氨酸是否对d-丝氨酸合成至关重要。该酶通过磷酸化途径催化l-丝氨酸合成的第一步。丝氨酸对映体的HPLC分析表明，条件敲除小鼠的大脑皮层和海马中l-丝氨酸和d-丝氨酸水平显著降低，而丝氨酸缺乏并未改变这些区域丝氨酸消旋酶和NMDA受体亚基的蛋白表达水平。本研究提供了明确的证据，证明通过磷酸化途径内源性合成的l-丝氨酸是维持成人大脑d-丝氨酸稳态水平的关键限速因素。此外，在条件敲除小鼠的海马体中，nmda诱发的直接早期基因Arc的转录减少。因此，本研究表明，在成熟的神经元回路中，l-丝氨酸的可用性决定了前脑中d-丝氨酸的合成速率，并至少在海马中控制NMDA受体的功能。
In mammalian brain, d-serine is synthesized from l-serine by serine racemase, and it functions as an obligatory co-agonist at the glycine modulatory site of N-methyl-d-aspartate (NMDA)-selective glutamate receptors. Although diminution in d-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor l-serine and its role in d-serine metabolism in adult brain have yet to be determined. We investigated whether l-serine synthesized in brain via the phosphorylated pathway is essential for d-serine synthesis by generating mice with a conditional deletion of d-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in l-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both l- and d-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that l-serine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steady-state levels of d-serine in adult brain. Furthermore, NMDA-evoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits l-serine availability determines the rate of d-serine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.