title: Glycolytic flux controls D-serine synthesis through glyceraldehyde-3-phosphate dehydrogenase in astrocytes.
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.
authors: Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan;
authors: Masataka
authors: M
authors: Suzuki
authors: Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan; sasabe@a8.keio.jp.
authors: Jumpei
authors: J
authors: Sasabe
authors: Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors: Yurika
authors: Y
authors: Miyoshi
authors: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan; RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; and.
authors: Kanako
authors: K
authors: Kuwasako
authors: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan; RIKEN Center for Life Science Technologies, Yokohama 230-0045, Japan; and.
authors: Yutaka
authors: Y
authors: Muto
authors: Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors: Kenji
authors: K
authors: Hamase
authors: Department of Pharmacology, Tokyo Medical University, Tokyo 160-8402, Japan.
authors: Masaaki
authors: M
authors: Matsuoka
authors: Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan;
authors: Nobuaki
authors: N
authors: Imanishi
authors: Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan;
authors: Sadakazu
authors: S
authors: Aiso
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009249:NADP / Q000235:genetics / Q000378:metabolism; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis* / Q000235:genetics; D009435:Synaptic Transmission / Q000502:physiology; D000099300:Serine Racemase
chemical_list: D000255:Adenosine Triphosphate; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D009249:NADP; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase
keywords: NADH; d-serine; glyceraldehyde-3-phosphate dehydrogenase; glycolysis; serine racemase