Serine Racemase

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Herman Wolosker - One of the best experts on this subject based on the ideXlab platform.

  • Serine Racemase deletion affects the excitatory inhibitory balance of the hippocampal ca1 network
    International Journal of Molecular Sciences, 2020
    Co-Authors: Eva Ploux, Herman Wolosker, Inna Radzishevsky, Valentine Bouet, Thomas Freret, Jeanmarie Billard
    Abstract:

    d-Serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the Serine Racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-Serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies. On the one hand, our extracellular recordings in hippocampal slices show that neither isolated NMDAR synaptic potentials nor LTP were altered in SR-KO mice. This was associated with a compensatory increase in hippocampal levels of glycine, another physiologic NMDAR co-agonist. SR-KO mice displayed no deficits in spatial learning, reference memory and cognitive flexibility. On the other hand, SR-KO mice showed a weaker LTP and a lower increase in NMDAR potentials compared to controls when GABAA receptors were pharmacologically blocked. Our results indicate that depletion of endogenous D-Serine caused a reduced inhibitory activity in CA1 hippocampal networks, altering the excitatory/inhibitory balance, which contributes to preserve functional plasticity at synapses and to maintain related cognitive abilities.

  • Serine Racemase and d Serine in the amygdala are dynamically involved in fear learning
    Biological Psychiatry, 2018
    Co-Authors: Darrick T. Balu, Herman Wolosker, Joseph T. Coyle, Kendall Taylor Presti, Cathy C Y Huang, Kevin Muszynski, Inna Radzishevsky, Guia Guffanti, Kerry J Ressler
    Abstract:

    Abstract Background The amygdala is a central component of the neural circuitry that underlies fear learning. N-methyl-D-aspartate receptor–dependent plasticity in the amygdala is required for pavlovian fear conditioning and extinction. N-methyl-D-aspartate receptor activation requires the binding of a coagonist, D-Serine, which is synthesized from L-Serine by the neuronal enzyme Serine Racemase (SR). However, little is known about SR and D-Serine function in the amygdala. Methods We used immunohistochemical methods to characterize the cellular localization of SR and D-Serine in the mouse and human amygdala. Using biochemical and molecular techniques, we determined whether trace fear conditioning and extinction engages the SR/D-Serine system in the brain. D-Serine was administered systemically to mice to evaluate its effect on fear extinction. Finally, we investigated whether the functional single nucleotide polymorphism rs4523957, which is an expression quantitative trait locus of the human Serine Racemase (SRR) gene, was associated with fear-related phenotypes in a highly traumatized human cohort. Results We demonstrate that approximately half of the neurons in the amygdala express SR, including both excitatory and inhibitory neurons. We find that the acquisition and extinction of fear memory engages the SR/D-Serine system in the mouse amygdala and that D-Serine administration facilitates fear extinction. We also demonstrate that the SRR single nucleotide polymorphism, rs4523957, is associated with posttraumatic stress disorder in humans, consistent with the facilitatory effect of D-Serine on fear extinction. Conclusions These new findings have important implications for understanding D-Serine–mediated N-methyl-D-aspartate receptor plasticity in the amygdala and how this system could contribute to disorders with maladaptive fear circuitry.

  • Serine Racemase an unconventional enzyme for an unconventional transmitter
    Amino Acids, 2012
    Co-Authors: Herman Wolosker, Hisashi Mori
    Abstract:

    The discovery of large amounts of d-Serine in the brain challenged the dogma that only l-amino acids are relevant for eukaryotes. The levels of d-Serine in the brain are higher than many l-amino acids and account for as much as one-third of l-Serine levels. Several studies in the last decades have demonstrated a role of d-Serine as an endogenous agonist of N-methyl-d-aspartate receptors (NMDARs). d-Serine is required for NMDAR activity during normal neurotransmission as well as NMDAR overactivation that takes place in neurodegenerative conditions. Still, there are many unanswered questions about d-Serine neurobiology, including regulation of its synthesis, release and metabolism. Here, we review the mechanisms of d-Serine synthesis by Serine Racemase and discuss the lessons we can learn from Serine Racemase knockout mice, focusing on the roles attributed to d-Serine and its cellular origin.

  • Serine Racemase and the Serine shuttle between neurons and astrocytes.
    Biochimica et Biophysica Acta, 2011
    Co-Authors: Herman Wolosker
    Abstract:

    Abstract d -Serine is a brain-enriched d -amino acid that works as a transmitter-like molecule by physiologically activating NMDA receptors. Synthesis of d -Serine is carried out by Serine Racemase (SR), a pyridoxal 5′-phosphate-dependent enzyme. In addition to carry out racemization, SR α,β-eliminates water from l - or d -Serine, generating pyruvate and NH4+. Here I review the main mechanisms regulating SR activity and d -Serine dynamics in the brain. I propose a role for SR in a novel form of astrocyte-neuron communication—the “Serine shuttle”, whereby astrocytes synthesize and export l -Serine required for the synthesis of d -Serine by the predominantly neuronal SR. d -Serine synthesized and released by neurons can be further taken up by astrocytes for storage and activity-dependent release. I discuss how SR α,β-elimination with d -Serine itself may limit the achievable intracellular d -Serine concentration, providing a mechanistic rationale on why neurons do not store as much d -Serine as astrocytes. The higher content of d -Serine in astrocytes appears to be related to increased d -Serine stability, for their low SR expression will prevent substantial d -Serine metabolism via α,β-elimination. SR and the Serine shuttle pathway are therapeutic targets in neurodegenerative diseases in which NMDA receptor dysfunction plays pathological roles. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology.

  • Phosphorylation of mouse Serine Racemase regulates D-Serine synthesis
    FEBS Letters, 2010
    Co-Authors: Veronika N. Foltyn, Martin Zehl, Elena Dikopoltsev, Ole Nørregaard Jensen, Herman Wolosker
    Abstract:

    Serine Racemase (SR) catalyses the synthesis of the transmitter/neuromodulator d-Serine, which plays a major role in synaptic plasticity and N-methyl d-aspartate receptor neurotoxicity. We now report that SR is phosphorylated at Thr71 and Thr227 as revealed by mass spectrometric analysis and in vivo phosphorylation assays. Thr71 phosphorylation was observed in the cytosolic and membrane-bound SR while Thr227 phosphorylation was restricted to the membrane fraction. The Thr71 site has a motif for proline-directed kinases and is the main phosphorylation site of SR. Experiments with a phosphorylation-deficient SR mutant indicate that Thr71 phosphorylation increases SR activity, suggesting a novel mechanism for regulating d-Serine production.

Joseph T. Coyle - One of the best experts on this subject based on the ideXlab platform.

  • factors regulating Serine Racemase and d amino acid oxidase expression in the mouse striatum
    Brain Research, 2021
    Co-Authors: Shunsuke Takagi, Darrick T. Balu, Joseph T. Coyle
    Abstract:

    Abstract d -Serine plays an important role in modulating N-methyl- d -aspartate receptor (NMDAR) neurotransmission in the mammalian brain by binding to the receptor’s glycine modulatory site (GMS). The cytosolic enzyme Serine Racemase (SR) converts L-Serine to d -Serine, while the peroxisomal enzyme d -amino acid oxidase (DAAO) catalyzes the breakdown of d -Serine. Although it is important to understand how the activities of SR and DAAO regulate d -Serine levels, very little is known about the mechanisms that regulate the expression of SR and DAAO. In this study, we investigated whether the different centrally active drugs affect the expression of SR and DAAO in adult mouse brain. We found that the NMDAR antagonist, MK801, and cocaine, psychotropic drugs that both augment glutamate release, reduce the expression of SR and DAAO. This regulation is brain region selective, and in the case of cocaine, is reversed in part byα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). However, d -Serine and antipsychotics do not regulate SR and DAAO protein levels. In a genetic model of SR disruption, we found that DAAO expression was unaltered in SR conditional knockout mice, in which tissue d -Serine content remains fairly stable despite marked reduction in SR expression. This study reveals a new mechanism by which AMPAR activity could regulate NMDAR function via d -Serine availability.

  • postsynaptic Serine Racemase regulates nmda receptor function
    The Journal of Neuroscience, 2020
    Co-Authors: Jonathan M Wong, Darrick T. Balu, Joseph T. Coyle, Oluwarotimi Folorunso, Eden V Barragan, Cristina Berciu, Theresa L Harvey, John A Gray
    Abstract:

    d-Serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme Serine Racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-Serine remains limited. Though early studies suggested d-Serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-Serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional knockout mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at one month of age, which could be rescued by exogenous d-Serine. Interestingly, there was a restoration of LTP by two months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-Serine action. SIGNIFICANCE STATEMENT NMDA receptors (NMDARs) are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a co-agonist, which is d-Serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-Serine availability remains limited. d-Serine is synthesized in the brain by the neuronal enzyme Serine Racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-Serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-Serine action at synapses.

  • postsynaptic Serine Racemase regulates nmda receptor function
    The Journal of Neuroscience, 2020
    Co-Authors: Jonathan M Wong, Darrick T. Balu, Joseph T. Coyle, Oluwarotimi Folorunso, Eden V Barragan, Cristina Berciu, Theresa L Harvey, John A Gray
    Abstract:

    d-Serine is the primary NMDAR coagonist at mature forebrain synapses and is synthesized by the enzyme Serine Racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-Serine remains limited. Though early studies suggested d-Serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-Serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional KO mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-Serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-Serine action.SIGNIFICANCE STATEMENT NMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which is d-Serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-Serine availability remains limited. d-Serine is synthesized in the brain by the neuronal enzyme Serine Racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-Serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-Serine action at synapses.

  • postsynaptic Serine Racemase regulates nmda receptor function
    bioRxiv, 2020
    Co-Authors: Jonathan M Wong, Oluwarotimi Folorunso, Eden V Barragan, Cristina Berciu, Theresa L Harvey, Michael R Dechellismarks, Jill R Glausier, Matthew L Macdonald, Joseph T. Coyle
    Abstract:

    Abstract D-Serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme Serine Racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic D-Serine remains limited. Though early studies suggested D-Serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and D-Serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons, as well as the presence of SR in human hippocampal synaptosomes. In addition, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at one month of age. Interestingly, there was a restoration of LTP by two months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of D-Serine action.

  • Serine Racemase Expression by Striatal Neurons
    Cellular and Molecular Neurobiology, 2020
    Co-Authors: Shunsuke Takagi, Darrick T. Balu, Matthew D. Puhl, Thea Anderson, Joseph T. Coyle
    Abstract:

    d -Serine is synthesized by Serine Racemase (SR) and is a co-agonist at forebrain N -methyl- d -aspartate receptors (NMDARs). d -Serine and SR are expressed primarily in neurons, but not in quiescent astrocytes. In this study, we examined the localization of d -Serine and SR in the mouse striatum and the effects of genetically silencing SR expression in GABAergic interneurons (iSR−/−). iSR−/− mice had substantially reduced SR expression almost exclusively in striatum, but only exhibited marginal d -Serine reduction. SR positive cells in the striatum showed strong co-localization with dopamine- and cyclic AMP-regulated neuronal phosphoprotein (DARPP32) in wild type mice. Transgenic fluorescent reporter mice for either the D1 or D2 dopamine receptors exhibited a 65:35 ratio for co-localization with D1and D2 receptor positive cells, respectively. These results indicate that GABAergic medium spiny neurons receiving dopaminergic inputs in striatum robustly and uniformly express SR. In behavioral tests, iSR−/− mice showed a blunted response to the hedonic and stimulant effects of cocaine, without affecting anxiety-related behaviors. Because the cocaine effects have been shown in the constitutive SR−/− mice, the restriction of the blunted response to cocaine to iSR−/− mice reinforces the conclusion that d -Serine in striatal GABAergic neurons plays an important role in mediating dopaminergic stimulant effects. Results in this study suggest that SR in striatal GABAergic neurons is synthesizing d -Serine, not as a glutamatergic co-transmitter, but rather as an autocrine whereby the GABAergic neurons control the excitability of their NMDARs by determining the availability of the co-agonist, d -Serine.

Andrea Mozzarelli - One of the best experts on this subject based on the ideXlab platform.

  • the allosteric interplay between s nitrosylation and glycine binding controls the activity of human Serine Racemase
    FEBS Journal, 2021
    Co-Authors: Francesco Marchesani, Serena Faggiano, Barbara Campanini, Andrea Mozzarelli, Stefano Bettati, Francesca Spyrakis, Eleonora Gianquinto, Ida Autiero, Annalisa Michielon, Stefano Bruno
    Abstract:

    Human Serine Racemase (hSR) catalyzes the biosynthesis of D-Serine, an obligatory co-agonist of the NMDA receptors. It was previously found that the reversible S-nitrosylation of Cys113 reduces hSR activity. Here, we show by site-directed mutagenesis, fluorescence spectroscopy, mass spectrometry, and molecular dynamics that S-nitrosylation stabilizes an open, less-active conformation of the enzyme. The reaction of hSR with either NO or nitroso donors is conformation-dependent and occurs only in the conformation stabilized by the allosteric effector ATP, in which the e-amino group of Lys114 acts as a base towards the thiol group of Cys113. In the closed conformation stabilized by glycine - an active-site ligand of hSR - the side chain of Lys114 moves away from that of Cys113, while the carboxyl side-chain group of Asp318 moves significantly closer, increasing the thiol pKa and preventing the reaction. We conclude that ATP binding, glycine binding, and S-nitrosylation constitute a three-way regulation mechanism for the tight control of hSR activity. We also show that Cys113 undergoes H2 O2 -mediated oxidation, with loss of enzyme activity, a reaction also dependent on hSR conformation.

  • The Energy Landscape of Human Serine Racemase
    Frontiers Media S.A., 2019
    Co-Authors: Samanta Raboni, Marialaura Marchetti, Serena Faggiano, Barbara Campanini, Stefano Bruno, Francesco Marchesani, Marilena Margiotta, Andrea Mozzarelli
    Abstract:

    Human Serine Racemase is a pyridoxal 5′-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L-Serine and D-Serine and their dehydration to pyruvate and ammonia. As D-Serine is the co-agonist of the N-methyl-D-aspartate receptors for glutamate, the most abundant excitatory neurotransmitter in the brain, the structure, dynamics, function, regulation and cellular localization of Serine Racemase have been investigated in detail. Serine Racemase belongs to the fold-type II of the PLP-dependent enzyme family and structural models from several orthologs are available. The comparison of structures of Serine Racemase co-crystallized with or without ligands indicates the presence of at least one open and one closed conformation, suggesting that conformational flexibility plays a relevant role in enzyme regulation. ATP, Mg2+, Ca2+, anions, NADH and protein interactors, as well as the post-translational modifications nitrosylation and phosphorylation, finely tune the Racemase and dehydratase activities and their relative reaction rates. Further information on Serine Racemase structure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human Serine Racemase allowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site

  • glutamine 89 is a key residue in the allosteric modulation of human Serine Racemase activity by atp
    Scientific Reports, 2018
    Co-Authors: Andrea Valeria Canosa, Marialaura Marchetti, Serena Faggiano, Barbara Campanini, Stefano Bruno, Stefano Armao, Stefano Bettati, Riccardo Percudani, Andrea Mozzarelli
    Abstract:

    Serine Racemase (SR) catalyses two reactions: the reversible racemisation of L-Serine and the irreversible dehydration of L- and D-Serine to pyruvate and ammonia. SRs are evolutionarily related to Serine dehydratases (SDH) and degradative threonine deaminases (TdcB). Most SRs and TdcBs – but not SDHs – are regulated by nucleotides. SR binds ATP cooperatively and the nucleotide allosterically stimulates the Serine dehydratase activity of the enzyme. A H-bond network comprising five residues (T52, N86, Q89, E283 and N316) and water molecules connects the active site with the ATP-binding site. Conservation analysis points to Q89 as a key residue for the allosteric communication, since its mutation to either Met or Ala is linked to the loss of control of activity by nucleotides. We verified this hypothesis by introducing the Q89M and Q89A point mutations in the human SR sequence. The allosteric communication between the active site and the allosteric site in both mutants is almost completely abolished. Indeed, the stimulation of the dehydratase activity by ATP is severely diminished and the binding of the nucleotide is no more cooperative. Ancestral state reconstruction suggests that the allosteric control by nucleotides established early in SR evolution and has been maintained in most eukaryotic lineages.

  • magnesium and calcium ions differentially affect human Serine Racemase activity and modulate its quaternary equilibrium toward a tetrameric form
    Biochimica et Biophysica Acta, 2017
    Co-Authors: Stefano Bruno, Serena Faggiano, Barbara Campanini, Francesco Marchesani, Marilena Margiotta, Valentina Orlandi, Gianluca Paredi, Luca Ronda, Andrea Mozzarelli
    Abstract:

    Abstract Serine Racemase is the pyridoxal 5′-phosphate dependent enzyme that catalyzes both production and catabolism of d -Serine, a co-agonist of the NMDA glutamate receptors. Mg 2 + , or, alternatively, Ca 2 + , activate human Serine Racemase by binding both at a specific site and – as ATP-metal complexes – at a distinct ATP binding site. We show that Mg 2 + and Ca 2 + bind at the metal binding site with a 4.5-fold difference in affinity, producing a similar thermal stabilization and partially shifting the dimer-tetramer equilibrium in favour of the latter. The ATP-Ca 2 + complex produces a 2-fold lower maximal activation in comparison to the ATP-Mg 2 + complex and exhibits a 3-fold higher EC 50 . The co-presence of ATP and metals further stabilizes the tetramer. In consideration of the cellular concentrations of Mg 2 + and Ca 2 + , even taking into account the fluctuations of the latter, these results point to Mg 2 + as the sole physiologically relevant ligand both at the metal binding site and at the ATP binding site. The stabilization of the tetramer by both metals and ATP-metal complexes suggests a quaternary activation mechanism mediated by 5′-phosphonucleotides similar to that observed in the distantly related prokaryotic threonine deaminases. This allosteric mechanism has never been observed before in mammalian fold type II pyridoxal 5′-phosphate dependent enzymes.

  • human Serine Racemase is allosterically modulated by nadh and reduced nicotinamide derivatives
    Biochemical Journal, 2016
    Co-Authors: Stefano Bruno, Serena Faggiano, Barbara Campanini, Francesco Marchesani, Marilena Margiotta, Luca Dellafiora, Andrea Mozzarelli
    Abstract:

    Serine Racemase catalyzes both the synthesis and the degradation of d-Serine, an obligatory co-agonist of the glutamatergic NMDA receptors. It is allosterically controlled by adenosine triphosphate (ATP), which increases its activity around 7-fold through a co-operative binding mechanism. Serine Racemase has been proposed as a drug target for the treatment of several neuropathologies but, so far, the search has been directed only toward the active site, with the identification of a few, low-affinity inhibitors. Following the recent observation that nicotinamide adenine dinucleotide (reduced form) (NADH) inhibits Serine Racemase, here we show that the inhibition is partial, with an IC50 of 246 ± 63 μM, several-fold higher than NADH intracellular concentrations. At saturating concentrations of NADH, ATP binds with a 2-fold lower affinity and without co-operativity, suggesting ligand competition. NADH also reduces the weak activity of human Serine Racemase in the absence of ATP, indicating an additional ATP-independent inhibition mechanism. By dissecting the NADH molecule, we discovered that the inhibitory determinant is the N-substituted 1,4-dihydronicotinamide ring. Particularly, the NADH precursor 1,4-dihydronicotinamide mononucleotide exhibited a partial mixed-type inhibition, with a KI of 18 ± 7 μM. Docking simulations suggested that all 1,4-dihydronicotinamide derivatives bind at the interdimeric interface, with the ring positioned in an unoccupied site next to the ATP-binding site. This newly recognized allosteric site might be exploited for the design of high-affinity Serine Racemase effectors to finely modulate d-Serine homeostasis.

Hisashi Mori - One of the best experts on this subject based on the ideXlab platform.

  • deletion of Serine Racemase confers d Serine dependent resilience to chronic social defeat stress
    Neurochemistry International, 2018
    Co-Authors: Chao Dong, Hisashi Mori, Qian Ren, Jichun Zhang, Kai Zhang, Wei Yao, Tamaki Ishima, Kenji Hashimoto
    Abstract:

    Abstract The N-methyl-D-aspartate receptor (NMDAR) plays a key role in the pathophysiology of depression. Serine Racemase (SRR, encoded by Srr) converts L-Serine to D-Serine, an endogenous co-agonist at the glycine site of the NMDAR. Knock-out (KO) of Srr did not alter behavioral signs of depression compared with wild-type (WT) mice as evaluated by locomotion, tail suspension, forced swimming, and 1% sucrose preference tests. However, chronic social defeat stress (CSDS: 10 days) caused a depression-like phenotype as measured by these same tests in WT mice but not in Srr KO mice, suggesting that decreased D-Serine co-agonist activity confers resilience against CSDS. In WT mice, CSDS decreased brain-derived neurotrophic factor (BDNF) expression and phosphorylation/activation of its receptor TrkB in prefrontal cortex (PFC), dentate gyrus (DG), and the CA3 region of the hippocampus, but increased BDNF and phosphorylated TrkB in the nucleus accumbens (NAc). Conversely, CSDS did not alter BDNF or TrkB phosphorylation in any brain region of Srr KO mice. Administration of D-Serine through drinking water (600 mg/L for 20 days) 10 days prior to and during CSDS restored the depression-like phenotype in Srr KO mice. These findings suggest that reducing brain D-Serine may improve stress resilience, thereby reducing depression risk.

  • Serine Racemase deletion attenuates neurodegeneration and microvascular damage in diabetic retinopathy
    PLOS ONE, 2018
    Co-Authors: Hironori Ozaki, Ran Inoue, Takako Matsushima, Masakiyo Sasahara, Atsushi Hayashi, Hisashi Mori
    Abstract:

    Diabetic retinopathy (DR) is a leading cause of blindness. DR is recognized as a microvascular disease and inner retinal neurodegeneration. In the course of retinal neurodegeneration, N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity is involved. Full activation of NMDAR requires binding of agonist glutamate and coagonist glycine or D-Serine. D-Serine is produced from L-Serine by Serine Racemase (SRR) and contributes to retinal neurodegeneration in rodent models of DR. However, the involvement of SRR in both neurodegeneration and microvascular damage in DR remains unclear. Here, we established diabetic model of SRR knockout (SRR-KO) and control wild-type (WT) mice by streptozotocin injection. Six months after the onset of diabetes, the number of survived retinal ganglion cells was higher in SRR-KO mice than that of WT mice. The reduction of thickness of inner retinal layer (IRL) was attenuated in SRR-KO mice than that of WT mice. Moreover, the number of damaged acellular capillaries was lower in SRR-KO mice than that of WT mice. Our results suggest the suppression of SRR activity may have protective effects in DR.

  • a novel Serine Racemase inhibitor suppresses neuronal over activation in vivo
    Bioorganic & Medicinal Chemistry, 2017
    Co-Authors: Hisashi Mori, Ryogo Wada, Tetsuya Ishimoto, Mineyuki Mizuguchi, Takayuki Obita, Satoyuki Takahara, Yoshikazu Horino, Hironori Izumi, Tomoyuki Yoshida, Hiroaki Gouda
    Abstract:

    Serine Racemase (SRR) is an enzyme that produces d-Serine from l-Serine. d-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs' over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states. In the previous study, we performed in silico screening to identify four compounds with inhibitory activities against recombinant SRR. Here, we synthesized 21 derivatives of candidate 1, one of four hit compounds, and performed screening by in vitro evaluations. The derivative 13J showed a significantly lower IC50 value in vitro, and suppressed neuronal over-activation in vivo.

  • Serine Racemase is involved in d aspartate biosynthesis
    Journal of Biochemistry, 2016
    Co-Authors: Tomokazu Ito, Tohru Yoshimura, Mika Hayashida, Saki Kobayashi, Natsumi Muto, Ayumi Hayashi, Hisashi Mori
    Abstract:

    d-Aspartate is found in the nervous and reproductive system and participates in various physiological roles. While several lines of evidence suggest that this amino acid has an endogenous origin, the enzyme responsible for mammalian d-Asp biosynthesis has not yet been identified. We show that mammalian Serine Racemase (SRR), the primary enzyme responsible for brain d-Ser production, catalyses Asp racemization via a two-base mechanism. We observed that overexpression of SRR in rat pheochromocytoma PC12 cells resulted in an increase in intracellular d-Asp compared with control cells, demonstrating that SRR functions as an Asp Racemase in the cells. To investigate the impact of endogenous SRR on endogenous d-Asp levels in the cells, we generated SRR-knockout (SRR-KO) PC12 cells. The SRR-KO cells exhibited decreased intracellular d-Ser levels, but production levels of d-Asp were unaffected. In contrast, SRR-KO mice showed significantly decreased d-Asp levels in their frontal cortices and hippocampi, where SRR is normally highly expressed, while d-Asp levels in the cerebellum and testes remained unchanged. Our results indicate that SRR indeed acts as a d-Asp biosynthetic enzyme in some organs and/or tissues, and also provide evidences that there should be some additional enzyme for d-Asp synthesis in mammals.

  • in silico and pharmacological screenings identify novel Serine Racemase inhibitors
    Bioorganic & Medicinal Chemistry Letters, 2014
    Co-Authors: Hisashi Mori, Ryogo Wada, Tetsuya Ishimoto, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka
    Abstract:

    Abstract d -Serine is a coagonist of the N-methyl- d -aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by Serine Racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50 value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.

Darrick T. Balu - One of the best experts on this subject based on the ideXlab platform.

  • factors regulating Serine Racemase and d amino acid oxidase expression in the mouse striatum
    Brain Research, 2021
    Co-Authors: Shunsuke Takagi, Darrick T. Balu, Joseph T. Coyle
    Abstract:

    Abstract d -Serine plays an important role in modulating N-methyl- d -aspartate receptor (NMDAR) neurotransmission in the mammalian brain by binding to the receptor’s glycine modulatory site (GMS). The cytosolic enzyme Serine Racemase (SR) converts L-Serine to d -Serine, while the peroxisomal enzyme d -amino acid oxidase (DAAO) catalyzes the breakdown of d -Serine. Although it is important to understand how the activities of SR and DAAO regulate d -Serine levels, very little is known about the mechanisms that regulate the expression of SR and DAAO. In this study, we investigated whether the different centrally active drugs affect the expression of SR and DAAO in adult mouse brain. We found that the NMDAR antagonist, MK801, and cocaine, psychotropic drugs that both augment glutamate release, reduce the expression of SR and DAAO. This regulation is brain region selective, and in the case of cocaine, is reversed in part byα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). However, d -Serine and antipsychotics do not regulate SR and DAAO protein levels. In a genetic model of SR disruption, we found that DAAO expression was unaltered in SR conditional knockout mice, in which tissue d -Serine content remains fairly stable despite marked reduction in SR expression. This study reveals a new mechanism by which AMPAR activity could regulate NMDAR function via d -Serine availability.

  • postsynaptic Serine Racemase regulates nmda receptor function
    The Journal of Neuroscience, 2020
    Co-Authors: Jonathan M Wong, Darrick T. Balu, Joseph T. Coyle, Oluwarotimi Folorunso, Eden V Barragan, Cristina Berciu, Theresa L Harvey, John A Gray
    Abstract:

    d-Serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme Serine Racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-Serine remains limited. Though early studies suggested d-Serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-Serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional knockout mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at one month of age, which could be rescued by exogenous d-Serine. Interestingly, there was a restoration of LTP by two months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-Serine action. SIGNIFICANCE STATEMENT NMDA receptors (NMDARs) are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a co-agonist, which is d-Serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-Serine availability remains limited. d-Serine is synthesized in the brain by the neuronal enzyme Serine Racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-Serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-Serine action at synapses.

  • postsynaptic Serine Racemase regulates nmda receptor function
    The Journal of Neuroscience, 2020
    Co-Authors: Jonathan M Wong, Darrick T. Balu, Joseph T. Coyle, Oluwarotimi Folorunso, Eden V Barragan, Cristina Berciu, Theresa L Harvey, John A Gray
    Abstract:

    d-Serine is the primary NMDAR coagonist at mature forebrain synapses and is synthesized by the enzyme Serine Racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-Serine remains limited. Though early studies suggested d-Serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-Serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional KO mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-Serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-Serine action.SIGNIFICANCE STATEMENT NMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which is d-Serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-Serine availability remains limited. d-Serine is synthesized in the brain by the neuronal enzyme Serine Racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-Serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-Serine action at synapses.

  • Serine Racemase Expression by Striatal Neurons
    Cellular and Molecular Neurobiology, 2020
    Co-Authors: Shunsuke Takagi, Darrick T. Balu, Matthew D. Puhl, Thea Anderson, Joseph T. Coyle
    Abstract:

    d -Serine is synthesized by Serine Racemase (SR) and is a co-agonist at forebrain N -methyl- d -aspartate receptors (NMDARs). d -Serine and SR are expressed primarily in neurons, but not in quiescent astrocytes. In this study, we examined the localization of d -Serine and SR in the mouse striatum and the effects of genetically silencing SR expression in GABAergic interneurons (iSR−/−). iSR−/− mice had substantially reduced SR expression almost exclusively in striatum, but only exhibited marginal d -Serine reduction. SR positive cells in the striatum showed strong co-localization with dopamine- and cyclic AMP-regulated neuronal phosphoprotein (DARPP32) in wild type mice. Transgenic fluorescent reporter mice for either the D1 or D2 dopamine receptors exhibited a 65:35 ratio for co-localization with D1and D2 receptor positive cells, respectively. These results indicate that GABAergic medium spiny neurons receiving dopaminergic inputs in striatum robustly and uniformly express SR. In behavioral tests, iSR−/− mice showed a blunted response to the hedonic and stimulant effects of cocaine, without affecting anxiety-related behaviors. Because the cocaine effects have been shown in the constitutive SR−/− mice, the restriction of the blunted response to cocaine to iSR−/− mice reinforces the conclusion that d -Serine in striatal GABAergic neurons plays an important role in mediating dopaminergic stimulant effects. Results in this study suggest that SR in striatal GABAergic neurons is synthesizing d -Serine, not as a glutamatergic co-transmitter, but rather as an autocrine whereby the GABAergic neurons control the excitability of their NMDARs by determining the availability of the co-agonist, d -Serine.

  • neurotoxic astrocytes express the d Serine synthesizing enzyme Serine Racemase in alzheimer s disease
    Neurobiology of Disease, 2019
    Co-Authors: Darrick T. Balu, Theresa L Harvey, Cathy C Y Huang, Kevin Muszynski, Harry Pantazopoulos, Yota Uno, Jacki M Rorabaugh, Claire R Galloway, Christian A Botzzapp
    Abstract:

    Although β-amyloid plaques are a well-recognized hallmark of Alzheimer's disease (AD) neuropathology, no drugs reducing amyloid burden have shown efficacy in clinical trials, suggesting that once AD symptoms emerge, disease progression becomes independent of Aβ production. Reactive astrocytes are another neuropathological feature of AD, where there is an emergence of neurotoxic (A1) reactive astrocytes. We find that Serine Racemase (SR), the neuronal enzyme that produces the N-methyl-d-aspartate receptor (NMDAR) co-agonist d-Serine, is robustly expressed in A1-reactive neurotoxic astrocytes in the hippocampus and entorhinal cortex of AD subjects and an AD rat model. Furthermore, we observe intracellular signaling changes consistent with increased extra-synaptic NMDAR activation, excitotoxicity and decreased neuronal survival. Thus, reducing neurotoxic d-Serine release from A1 inflammatory astrocytes could have therapeutic benefit for mild to advanced AD, when anti-amyloid strategies are ineffective.

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