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.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...

Time and space profiling of NMDA receptor co‐agonist functions

“…Accordingly, (Suzuki et al . ) using SR‐KO as negative controls recently report that astrocytes abundantly express SR in the human subiculum thus supporting the notion that SR and d ‐serine are present in astrocytes in vivo (Ma et al ., , Martineau et al ., ). Thus, the cellular distribution of SR remains an open issue particularly as a recent transcriptome analysis of isolated purified brain cell groups shows that the enzyme is more expressed in glia cell lineage and notably astrocytes than in neurons in the mature cortex of mice (Zhang et al .…”

Glyceraldehyde‐3‐phosphate dehydrogenase promotes liver tumorigenesis by modulating phosphoglycerate dehydrogenase

“…). Previously, GAPDH has been reported to control d ‐serine production in the hippocampus by interacting with serine racemase, which converts l ‐serine into d ‐serine, thereby influencing glutamatergic neurotransmission . Serine metabolism is critical for cancer cells, and the diversion of glycolytic flux to serine metabolism contributes to tumor progression .…”

The Rise and Fall of the d -Serine-Mediated Gliotransmission Hypothesis

“…SR was virtually completely neuronal, with only trace astrocytic expression in the cortex and hippocampus [31]. Recently, low astrocytic SR staining was detectable in mouse hippocampus, only after the use of an amplification method [32], confirming the scarcity of astrocytic SR in vivo . Furthermore, Balu et al used an SR antibody validated with brain tissue from SR−/− mice and found that SR was expressed in pyramidal and inhibitory neurons but not in S100β–containing astrocytes in human primary motor cortex [33].…”