Modulation of D-Serine Levels via Ubiquitin-dependent Proteasomal Degradation of Serine Racemase

Dumin, Elena; Bendikov, Inna; Foltyn, Veronika N.; Misumi, Yoshio; Ikehara, Yukio; Kartvelishvily, Elena; Wolosker, Herman

doi:10.1074/jbc.m601971200

Cited by 60 publications

(61 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SRR requires pyridoxal phosphate and also has an absolute requirement for ATP (14,15). SRR is regulated by interacting proteins, including glutamate receptor interacting protein (GRIP) (16), protein interacting with PRKCA 1 (17), disrupted in schizophrenia 1 (18), and golgin A3 (19). It is also known that the enzymatic activity of SRR is inhibited by nitric oxide in presynaptic neurons (20) and by phosphatidylinositol (4, 5)-bisphosphate (PIP2) in astrocytes (21), both of which are involved in feedback regulation via glutamate receptors.…”

mentioning

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.

View full text Add to dashboard Cite

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...

show abstract

mentioning

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.

View full text Add to dashboard Cite

show abstract

“…D-serine is synthesized by serine racemase (SR), an enzyme that directly converts L-into D-serine (6). This enzyme is regulated by interacting proteins, such as the glutamate interacting protein 1 (5), Pick-1 (7), and Golga3 (8), and by nitric oxide produced upon NMDAR activation (9).…”

mentioning

confidence: 99%

Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane

Balan

Foltyn²,

Zehl³

et al. 2009

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

Self Cite

View full text Add to dashboard Cite

D-serine is a physiological coagonist of N-methyl D-aspartate receptors (NMDARs) that plays a major role in several NMDARdependent events. In this study we investigate mechanisms regulating D-serine production by the enzyme serine racemase (SR). We now report that NMDAR activation promotes translocation of SR to the plasma membrane, which dramatically reduces the enzyme activity. Membrane-bound SR isolated from rat brain is not extracted from the membrane by high detergent and salt concentration, indicating a strong association. Colocalization studies indicate that most membrane-bound SR is located at the plasma membrane and dendrites, with much less SR observed in other types of membrane. NMDAR activation promotes translocation of the cytosolic SR to the membrane, resulting in reduced D-serine synthesis, and this effect is averted by blockade of NMDARs. In primary neuronal cultures, SR translocation to the membrane is blocked by a palmitoylation inhibitor, indicating that membrane binding is mediated by fatty acid acylation of SR. In agreement, we found that SR is acylated in transfected neuroblastoma cells using [ 3 H]palmitate or [ 3 H]octanoic acid as precursors. In contrast to classical S-palmitoylation of cysteines, acylation of SR occurs through the formation of an oxyester bond with serine or threonine residues. In addition, we show that phosphorylation of Thr-227 is also required for steady-state binding of SR to the membrane under basal, nonstimulated condition. We propose that the inhibition of D-serine synthesis caused by translocation of SR to the membrane provides a fail-safe mechanism to prevent NMDAR overactivation in vicinal cells or synapses.glutamate ͉ neurotransmission ͉ octanoylation ͉ palmitoylation ͉ synapse D -serine is a physiological ligand of the coagonist site of NMDARs, mediating several NMDAR-dependent events, including NMDAR neurotransmission (1), neurotoxicity (2, 3), synaptic plasticity (4), and cell migration (5). D-serine is synthesized by serine racemase (SR), an enzyme that directly converts L-into D-serine (6). This enzyme is regulated by interacting proteins, such as the glutamate interacting protein 1 (5), Pick-1 (7), and Golga3 (8), and by nitric oxide produced upon NMDAR activation (9).Despite the many roles attributed to it, the regulation of D-serine signaling is still largely unknown. Furthermore, many questions remain unresolved regarding the distribution of SR and the roles played by glia vs. neurons in D-serine signaling (10). Although the highest levels of endogenous D-serine were shown to be present in brain astrocytes (11), D-serine has also been detected in neurons (2). Recent data using new antibodies against SR (2) and SR knockout mice as negative controls (12) indicate that SR is abundantly expressed in neurons, with highest levels in the cerebral cortex and the hippocampal formation. Moreover, endogenous D-serine released from neuronal cultures lacking significant levels of astrocytes mediates NMDAR-elicited neurotoxicity (2), suggesting that neuron-derived...

show abstract

“…Neuronal SR activity is reduced by interaction with the synaptic protein Stargazin (21). In neurons, D-serine synthesis is enhanced by FBXO22, which prevents the association of SR to intracellular membranes (22), and by Golga3, which reduces the degradation of SR by the ubiquitin system (23). SR knock-out (KO) mice display phenotypic abnormalities compatible with NMDAR hypofunction (24 -26).…”

mentioning

confidence: 99%

Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production

Kolodney

Dumin

Safory

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

D-Serine is a physiological co-agonist that activates N-methyl D-aspartate receptors (NMDARs) and is essential for neurotransmission, synaptic plasticity, and behavior. D-Serine may also trigger NMDAR-mediated neurotoxicity, and its dysregulation may play a role in neurodegeneration. D-Serine is synthesized by the enzyme serine racemase (SR), which directly converts L-serine to D-serine. However, many aspects concerning the regulation of D-serine production under physiological and pathological conditions remain to be elucidated. Here, we investigate possible mechanisms regulating the synthesis of D-serine by SR in paradigms relevant to neurotoxicity. We report that SR undergoes nucleocytoplasmic shuttling and that this process is dysregulated by several insults leading to neuronal death, typically by apoptotic stimuli. Cell death induction promotes nuclear accumulation of SR, in parallel with the nuclear translocation of GAPDH and Siah proteins at an early stage of the cell death process. Mutations in putative SR nuclear export signals (NESs) elicit SR nuclear accumulation and its depletion from the cytosol. Following apoptotic insult, SR associates with nuclear GAPDH along with other nuclear components, and this is accompanied by complete inactivation of the enzyme. As a result, extracellular D-serine concentration is reduced, even though extracellular glutamate concentration increases severalfold. Our observations imply that nuclear translocation of SR provides a fail-safe mechanism to prevent or limit secondary NMDAR-mediated toxicity in nearby synapses.

show abstract

Modulation of D-Serine Levels via Ubiquitin-dependent Proteasomal Degradation of Serine Racemase

Cited by 60 publications

References 46 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

Feedback inactivation of D-serine synthesis by NMDA receptor-elicited translocation of serine racemase to the membrane

Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production

Contact Info

Product

Resources

About