期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：E2217-E2224
DOI：10.1073/pnas.1416117112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNeurons require enormous energy to maintain continuous neurotransmission. To meet this requirement, astrocytes support neurons by balancing glycolytic flux with the synaptic level of an excitatory neurotransmitter, glutamate. But to control NMDA-subtype glutamate receptors, regulation of a coagonist, D-serine, as well as of glutamate, is crucial. Here we report that a glycolytic enzyme regulates D-serine synthesis as an indicator of glycolytic activity in astrocytes. This study shows how glutamatergic neurotransmission accommodates to changing energy circumstances through the coagonist. 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.
