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

Jung Hoon Yang, Akira Wada, Kazuyuki Yoshida, Yurika Miyoshi, Tomoko Sayano, Kayoko Esaki, Masami O. Kinoshita, Shozo Tomonaga, Norihiro Azuma, Masahiko Watanabe, Kenji Hamase, Kiyoshi Zaitsu, Takeo MacHida, Albee Messing, Shigeyoshi Itohara, Yoshio Hirabayashi, Shigeki Furuya

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist 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 Dserine 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 Lserine- synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked 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 Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.

Original languageEnglish
Pages (from-to)41380-41390
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number53
DOIs
Publication statusPublished - Dec 31 2010

Fingerprint

Biosynthesis
N-Methyl-D-Aspartate Receptors
Serine
Brain
Hippocampus
Knockout Mice
Phosphoglycerate Dehydrogenase
Immediate-Early Genes
Enantiomers
Glutamate Receptors
N-Methylaspartate
Transcription
Prosencephalon
Metabolism
Cerebral Cortex
Glycine
Schizophrenia
Genes
High Pressure Liquid Chromatography
Availability

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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. / Yang, Jung Hoon; Wada, Akira; Yoshida, Kazuyuki; Miyoshi, Yurika; Sayano, Tomoko; Esaki, Kayoko; Kinoshita, Masami O.; Tomonaga, Shozo; Azuma, Norihiro; Watanabe, Masahiko; Hamase, Kenji; Zaitsu, Kiyoshi; MacHida, Takeo; Messing, Albee; Itohara, Shigeyoshi; Hirabayashi, Yoshio; Furuya, Shigeki.

In: Journal of Biological Chemistry, Vol. 285, No. 53, 31.12.2010, p. 41380-41390.

Research output: Contribution to journalArticle

Yang, JH, Wada, A, Yoshida, K, Miyoshi, Y, Sayano, T, Esaki, K, Kinoshita, MO, Tomonaga, S, Azuma, N, Watanabe, M, Hamase, K, Zaitsu, K, MacHida, T, Messing, A, Itohara, S, Hirabayashi, Y & Furuya, S 2010, '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', Journal of Biological Chemistry, vol. 285, no. 53, pp. 41380-41390. https://doi.org/10.1074/jbc.M110.187443
Yang, Jung Hoon ; Wada, Akira ; Yoshida, Kazuyuki ; Miyoshi, Yurika ; Sayano, Tomoko ; Esaki, Kayoko ; Kinoshita, Masami O. ; Tomonaga, Shozo ; Azuma, Norihiro ; Watanabe, Masahiko ; Hamase, Kenji ; Zaitsu, Kiyoshi ; MacHida, Takeo ; Messing, Albee ; Itohara, Shigeyoshi ; Hirabayashi, Yoshio ; Furuya, Shigeki. / 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. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 53. pp. 41380-41390.
@article{080e1359001045699e49c955aa7350e4,
title = "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",
abstract = "In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist 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 Dserine 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 Lserine- synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked 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 Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.",
author = "Yang, {Jung Hoon} and Akira Wada and Kazuyuki Yoshida and Yurika Miyoshi and Tomoko Sayano and Kayoko Esaki and Kinoshita, {Masami O.} and Shozo Tomonaga and Norihiro Azuma and Masahiko Watanabe and Kenji Hamase and Kiyoshi Zaitsu and Takeo MacHida and Albee Messing and Shigeyoshi Itohara and Yoshio Hirabayashi and Shigeki Furuya",
year = "2010",
month = "12",
day = "31",
doi = "10.1074/jbc.M110.187443",
language = "English",
volume = "285",
pages = "41380--41390",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "53",

}

TY - JOUR

T1 - 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

AU - Yang, Jung Hoon

AU - Wada, Akira

AU - Yoshida, Kazuyuki

AU - Miyoshi, Yurika

AU - Sayano, Tomoko

AU - Esaki, Kayoko

AU - Kinoshita, Masami O.

AU - Tomonaga, Shozo

AU - Azuma, Norihiro

AU - Watanabe, Masahiko

AU - Hamase, Kenji

AU - Zaitsu, Kiyoshi

AU - MacHida, Takeo

AU - Messing, Albee

AU - Itohara, Shigeyoshi

AU - Hirabayashi, Yoshio

AU - Furuya, Shigeki

PY - 2010/12/31

Y1 - 2010/12/31

N2 - In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist 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 Dserine 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 Lserine- synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked 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 Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.

AB - In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist 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 Dserine 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 Lserine- synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked 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 Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.

UR - http://www.scopus.com/inward/record.url?scp=78650664020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650664020&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.187443

DO - 10.1074/jbc.M110.187443

M3 - Article

VL - 285

SP - 41380

EP - 41390

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 53

ER -