Alteration of intrinsic amounts of d-serine in the mice lacking serine racemase and d-amino acid oxidase

Miyoshi, Y.; Konno, Ryuichi; Sasabe, Jumpei; Ueno, Kyoko; Tojo, Yosuke; Mita, Masashi; Aiso, Sadakazu; Hamase, Kenji

doi:10.1007/s00726-012-1398-4

Cited by 46 publications

(40 citation statements)

References 50 publications

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“…Crlj:CD-1 (ICR) mice were purchased from Charles River Laboratories Japan. SRR knockout mice were kindly provided by Dr Ryuichi Konno (47). All animal experiments were approved by Keio University's Institutional Animal Experiment Committee.…”

Section: Methodsmentioning

confidence: 99%

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

Suzuki

Sasabe

Miyoshi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.eurons require a great deal of energy owing to their continuous need for ion gradient restoration across the cell membrane. Recent advances in the field of brain energy metabolism strongly suggest that glutamatergic neurotransmission is coupled with molecular signals that switch on glucose utilization pathways to meet this requirement. Astrocytes are key to the energy supply for neurons through the regulation of synaptic glutamate. Astrocytic glutamate uptake drives glycolysis, as well as the subsequent shuttling of lactate from astrocytes to neurons for oxidative metabolism (1-4). Astrocytes also store brain energy currency in the form of glycogen, which can be mobilized to produce lactate for neuronal oxidative phosphorylation (OXPHOS) in response to glutamatergic neurotransmission. Inhibiting glutamate uptake in astrocytes prevents the stimulation of the glycolytic pathway mediated by glutamate (5, 6). In contrast, inhibiting glycolysis impairs glutamate transport or even releases glutamate to the extracellular space (7,8). These mechanisms suggest that glycolytic metabolism is involved in regulating synaptic glutamate levels and, consequently, in excitatory neurotransmission.N-methyl-D-aspartate (NMDA) types of glutamate receptors have principal roles in excitatory neurotransmission and participate in numerous physiological processes, including learning and memory. Activity of the NMDA receptor is tightly regulated, and its overactivation contributes to such pathological conditions as stroke (9) and neurodegenerative diseases (10-12). NMDA receptors essentially require binding of a c...

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Section: Methodsmentioning

confidence: 99%

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

Suzuki

Sasabe

Miyoshi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The D-serine content in naïve SRR − / − mice has been reported to be almost 10% of that in WT mice. 12 If so, our data showed that the D-serine content in the SRR − / − brain remained at about the same level even at 20 hours after reperfusion, compared with the baseline. These findings also mean that a D-serine peak after reperfusion was not seen in SRR − / − mice.…”

Section: Discussionmentioning

confidence: 63%

Cellular Origin and Regulation of D-and L-Serine in in Vitro and in Vivo Models of Cerebral Ischemia

Abe

Suzuki

Sasabe

et al. 2014

J Cereb Blood Flow Metab

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D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-Serine from L-Serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-Serine remain elusive. The D-/L-Serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-Serine is derived from neurons, while L-Serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-Serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-Serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.

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“…Using Pirkle -type enantioselective columns, such as the Sumichiral OA-2500S and OA-3200S, a variety of NBD-proteinogenic amino acids could be separated [24][25][26][30][31][32][33]. By using the quinine based anion-exchange type chiral stationary phases, enantiomers of the NBD-amino acids were also nicely separated [27,34].…”

Section: Enantioselective Separation Of Extraterrestrial Amino Acids mentioning

confidence: 99%

Enantioselective Determination of Extraterrestrial Amino Acids Using a Two-Dimensional Chiral High-Performance Liquid Chromatographic System

et al. 2014

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A two-dimensional chiral high-performance liquid chromatographic (2D-HPLC) system has been established for the analysis of extraterrestrial amino acids. As the targets, 8 chiral amino acids (alanine (Ala), valine (Val), 2-aminobutyric acid (2AB), norvaline (nVal), N-methylalanine (N-MeAla), isovaline (iVal), 3AB and 3-aminoisobutyric acid (3AIB)) and 5 non-chiral amino acids (glycine (Gly), β-Ala, γ-aminobutyric acid (GABA), sarcosine (Sar) and 2AIB) were selected. These amino acids were tagged with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), and non-enantioselectively separated by a capillary monolithic ODS column in the first dimension. The target fractions were automatically introduced into the second dimension and further separated by Pirkle-type enantioselective columns. By using this system, the 2D-HPLC separation of 21 components in small particles of a carbonaceous chondrite (Yamato 791191, Antarctic CM2 meteorite) could be successfully performed, and all of the target amino acids were observed. The D/L ratios of the chiral molecules are almost 50/50 for all of the tested proteinogenic and non-proteinogenic amino acids.

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Alteration of intrinsic amounts of d-serine in the mice lacking serine racemase and d-amino acid oxidase

Cited by 46 publications

References 50 publications

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

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

Cellular Origin and Regulation of D-and L-Serine in in Vitro and in Vivo Models of Cerebral Ischemia

Enantioselective Determination of Extraterrestrial Amino Acids Using a Two-Dimensional Chiral High-Performance Liquid Chromatographic System

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