title: Nuclear Compartmentalization of Serine Racemase Regulates D-Serine Production: IMPLICATIONS FOR N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ACTIVATION.
abstract: 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.
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology and.
authors.forename: Goren
authors.initials: G
authors.lastname: Kolodney
authors.affiliation: the Laboratory of Clinical Biochemistry, Metabolic Unit, Rambam Health Care Campus, Haifa 31096, Israel, and.
authors.forename: Elena
authors.initials: E
authors.lastname: Dumin
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology and.
authors.forename: Hazem
authors.initials: H
authors.lastname: Safory
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology and.
authors.forename: Dina
authors.initials: D
authors.lastname: Rosenberg
authors.affiliation: the Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology and vinna@tx.technion.ac.il.
authors.forename: Inna
authors.initials: I
authors.lastname: Radzishevsky
authors.forename: Inna
authors.initials: I
authors.lastname: Radzishevisky
authors.affiliation: From the Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology and hwolosker@tx.technion.ac.il.
authors.forename: Herman
authors.initials: H
authors.lastname: Wolosker
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000201:enzymology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000096:biosynthesis* / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D000099300:Serine Racemase
chemical_list: D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D009687:Nuclear Proteins; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase
keywords: D-serine; N-methyl-d-aspartate receptor (NMDA receptor, NMDAR); apoptosis; cell death; excitotoxicity; glutamate receptor; glycine; neurotoxicity; nuclear translocation; serine racemase