Glycolytic flux controls D-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes

Masataka Suzuki, Jumpei Sasabe, Yurika Miyoshi, Kanako Kuwasako, Yutaka Muto, Kenji Hamase, Masaaki Matsuoka, Nobuaki Imanishi, Sadakazu Aiso

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

D-Serine is an essential coagonist with glutamate for stimulation of N-methyl-D-aspartate (NMDA) glutamate receptors. Although astrocytic metabolic processes are known to regulate synaptic glutamate levels, mechanisms that control D-serine levels are not well defined. Here we show that D-serine production in astrocytes is modulated by the interaction between the D-serine synthetic enzyme serine racemase (SRR) and a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). In primary cultured astrocytes, glycolysis activity was negatively correlated with D-serine level. We show that SRR interacts directly with GAPDH, and that activation of glycolysis augments this interaction. Biochemical assays using mutant forms of GAPDH with either reduced activity or reduced affinity to SRR revealed that GAPDH suppresses SRR activity by direct binding to GAPDH and through NADH, a product of GAPDH. NADH allosterically inhibits the activity of SRR by promoting the disassociation of ATP from SRR. Thus, astrocytic production of D-serine is modulated by glycolytic activity via interactions between GAPDH and SRR. We found that SRR is expressed in astrocytes in the subiculum of the human hippocampus, where neurons are known to be particularly vulnerable to loss of energy. Collectively, our findings suggest that astrocytic energy metabolism controls D-serine production, thereby influencing glutamatergic neurotransmission in the hippocampus.

Original languageEnglish
Pages (from-to)E2217-E2224
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number17
DOIs
Publication statusPublished - 2015 Apr 28
Externally publishedYes

Keywords

  • D-serine
  • Glyceraldehyde-3-phosphate dehydrogenase
  • Glycolysis
  • NADH
  • Serine racemase

ASJC Scopus subject areas

  • General

Cite this

Glycolytic flux controls D-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes. / Suzuki, Masataka; Sasabe, Jumpei; Miyoshi, Yurika; Kuwasako, Kanako; Muto, Yutaka; Hamase, Kenji; Matsuoka, Masaaki; Imanishi, Nobuaki; Aiso, Sadakazu.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 17, 28.04.2015, p. E2217-E2224.

Research output: Contribution to journalArticle

Suzuki, Masataka ; Sasabe, Jumpei ; Miyoshi, Yurika ; Kuwasako, Kanako ; Muto, Yutaka ; Hamase, Kenji ; Matsuoka, Masaaki ; Imanishi, Nobuaki ; Aiso, Sadakazu. / Glycolytic flux controls D-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 17. pp. E2217-E2224.
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AU - Muto, Yutaka

AU - Hamase, Kenji

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AU - Imanishi, Nobuaki

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AB - D-Serine is an essential coagonist with glutamate for stimulation of N-methyl-D-aspartate (NMDA) glutamate receptors. Although astrocytic metabolic processes are known to regulate synaptic glutamate levels, mechanisms that control D-serine levels are not well defined. Here we show that D-serine production in astrocytes is modulated by the interaction between the D-serine synthetic enzyme serine racemase (SRR) and a glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). In primary cultured astrocytes, glycolysis activity was negatively correlated with D-serine level. We show that SRR interacts directly with GAPDH, and that activation of glycolysis augments this interaction. Biochemical assays using mutant forms of GAPDH with either reduced activity or reduced affinity to SRR revealed that GAPDH suppresses SRR activity by direct binding to GAPDH and through NADH, a product of GAPDH. NADH allosterically inhibits the activity of SRR by promoting the disassociation of ATP from SRR. Thus, astrocytic production of D-serine is modulated by glycolytic activity via interactions between GAPDH and SRR. We found that SRR is expressed in astrocytes in the subiculum of the human hippocampus, where neurons are known to be particularly vulnerable to loss of energy. Collectively, our findings suggest that astrocytic energy metabolism controls D-serine production, thereby influencing glutamatergic neurotransmission in the hippocampus.

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