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PubMed1998

The stereo-specific effect of D-serine ethylester and the D-cycloserine in ataxic mutant mice.

Spinocerebellar ataxia is one of the most common neurological disorders. However, few therapeutics are effective for the treatment of this disorder. In the present study, we investigated the efficacy of d-serine ethylester and a related substance, d-cycloserine, as therapeutic agents for ataxia in a murine model. Both compounds are known to stereospecific modulate N-methyl-d-aspartate type glutamate receptors, and impaired glutamate-mediated signaling has been implicated in spinocerebellar ataxia. Using a microdialysis method, we found that intraperitoneal administration of d-serine ethylester increases the extracellular content of endogenous d-serine in the mouse cerebellum for at least 3 h. Maximum elevation of the extracellular d-serine was observed at 40 min after injection. An open-field study was used to assay the effect of the d-serine derivatives on movement and ataxia. In mice exhibiting cytosine arabinoside-induced ataxia, d-serine ethylester reduced the falling index in a dose-dependent manner. The effect of d-serine ethylester was stereo-specific in that l-serine ethylester had no effect on the falling index at the maximum doses tested, and was partially inhibited by 5,7-dichlorokynurenate, an antagonist that binds to the glycine-binding site. Locomotor activity was not changed by the d-serine ethylester treatment. d-cycloserine also significantly reduced the falling index of the mice. Both d-serine ethylester and d-cycloserine had longer lasting effects than other potential therapeutic reagents for ataxia. Growing evidence suggests the essential involvement of endogenous d-serine in mammalian brain function, and our results suggest that d-serine derivatives may represent an effective new therapeutic for the treatment of spinocerebellar ataxia.

Animals↗
PubMed1999

Ribonucleotide reductase R2 protein is phosphorylated at serine-20 by P34cdc2 kinase.

Ribonucleotide reductase is a rate-limiting enzyme in DNA synthesis and is composed of two different proteins, R1 and R2. The R2 protein appears to be rate-limiting for enzyme activity in proliferating cells, and it is phosphorylated by p34cdc2 and CDK2, mediators of cell cycle transition events. A sequence in the R2 protein at serine-20 matches a consensus sequence for p34cdc2 and CDK2 kinases. We tested the hypothesis that the serine-20 residue was the major p34cdc2 kinase site of phosphorylation. Three peptides were synthesized (from Asp-13 to Ala-28) that contained either the wild type amino acid sequence (Asp-Gln-Gln-Gln-Leu-Gln-Leu-Ser-Pro-Leu-Lys-Arg-Leu-Thr-Leu-Ala, serine peptide) or a mutation, in which the serine residue was replaced with an alanine residue (alanine peptide) or a threonine residue (threonine peptide). Only the serine peptide and threonine peptide were phosphorylated by p34cdc2 kinase. In two-dimensional phosphopeptide mapping experiments of serine peptide and Asp-N endoproteinase digested R2 protein, peptide co-migration patterns suggested that the synthetic phosphopeptide containing serine-20 was identical to the major Asp-N digested R2 phosphopeptide. To further test the hypothesis that serine-20 is the primary phosphorylated residue on R2 protein, three recombinant R2 proteins (R2-Thr, R2-Asp and R2-Ala) were generated by site-directed mutagenesis, in which the serine-20 residue was replaced with threonine, aspartic acid or alanine residues. Wild type R2 and threonine-substituted R2 proteins (R2-Thr) were phosphorylated by p34cdc2 kinase, whereas under the same experimental conditions, R2-Asp and R2-Ala phosphorylation was not detected. Furthermore, the phosphorylated amino acid residue in the R2-Thr protein was determined to be phosphothreonine. Therefore, by replacing a serine-20 residue with a threonine, the phosphorylated amino acid in R2 protein was changed to a phosphothreonine. In total, these results firmly establish that a major p34cdc2 phosphorylation site on the ribonucleotide reductase R2 protein occurs near the N-terminal end at serine-20, which is found within the sequence Ser-Pro-Leu-Lys-Arg-Leu. Comparison of ribonucleotide reductase activities between wild type and mutated forms of the R2 proteins suggested that mutation at serine-20 did not significantly affect enzyme activity.

Amino Acid Sequence↗
PubMed1974

Inhibition of growth of Mycobacterium smegmatis and of cell wall synthesis by D-serine.

d-Serine inhibited the growth of Mycobacterium smegmatis and induced the morphological alteration of the bacilli. The growth inhibitory action of d-serine was partially reduced by an equimolecular concentration of d-alanine. The combination of glycine with d-alanine reversed the growth inhibition produced by d-serine more than did d-alanine alone. In cells cultured in the presence of d-serine, the amounts of alanine, diaminopimelic acid, and glycine inserted into the cell wall mucopeptide were reduced, and serine was increased. The intracellular accumulation of a precursor of cell wall mucopeptide was increased by d-serine, and this accumulation was reduced by d-alanine. d-Serine competed with glycine for incorporation into the cell wall mucopeptide. The incorporation of l-aspartic acid into diaminopimelic acid residues in the cell wall mucopeptide was markedly inhibited by d-serine. Three mutants resistant to d-serine were isolated by nitrosoguanidine treatment. In these mutants the effects of d-serine on the sites of cell wall mucopeptide synthesis were all reduced. Thus, d-serine inhibition of the growth is due to replacement of glycine residues of the cell wall mucopeptide with d-serine and inhibition of the cell wall synthesis by blocking the formation of d-alanine and diaminopimelic acid.

Amino Acids↗
PubMed1972

Serine biosynthesis and its regulation in Bacillus subtilis.

Cell-free extracts of Bacillus subtilis strains GSY and 168 convert (14)C-phosphoglycerate to (14)C-serine phosphate and (14)C-serine. These reactions indicate a functional phosphorylated pathway for serine biosynthesis in these cells. The addition of serine to the incubation mixture inhibited the formation of both radioactive products. Extracts of mutant strains that require serine for growth lacked the capacity to synthesize serine phosphate, confirming that the phosphorylated pathway was the only functional pathway available for serine synthesis. Serine phosphate phosphatase and phosphoglycerate dehydrogenase activity were demonstrated in cell extracts, and the phosphoglycerate dehydrogenase was shown to be inhibited specifically by l-serine. The extent of serine inhibition increased when the temperature was raised from 25 to 37 C, and the thermal stability of the enzyme was enhanced by the presence of the inhibitor serine or the coenzyme reduced nicotinamide adenine dinucleotide. At 37 C the curve representing the relationship between phosphoglycerate concentration and enzyme velocity was biphasic, and the serine inhibition which was competitive at low substrate concentrations became noncompetitive at higher concentrations.

Ammonium Sulfate↗
PubMed1999

D-Serine is reabsorbed in rat renal pars recta.

D-Serine normally contributes up to 3% to total plasma serine and up to 23% in chronic renal failure. D-Serine is metabolized by tubular D-amino acid oxidase (D-AAO), and high D-serine plasma levels are nephrotoxic; both events are localized in the straight part of the proximal tubule. We therefore investigated if and how D-serine is reabsorbed there. We microinfused 14C-labeled D- or -L-serine + [3H]inulin into early proximal (EP), late proximal (LP), or early distal (ED) tubule sections of superficial nephrons and into long loops of Henle (LLH) of rats in vivo and in situ. The fractional reabsorption (FR) of the 14C label was determined from the 14C:3H ratio in the final urine. At 0.36 mM, FR of D-[14C]serine was 86% (EP), 90% (LP), and approximately 0 (ED, LLH). FR of D-serine could be saturated and inhibited by L-serine (and vice versa). D-methionine, but not D-glutamate or D-arginine, blocked FR of D-serine (LP). We conlude that filtered D-serine is able to enter the pars recta cells, thereby getting access to D-AAO. The uptake carrier has a very low stereospecificity and is, therefore, different from that in the proximal convolution. The colocalization of exclusive reabsorption and metabolism makes the pars recta the tubule site for the recycling of the carbon structure of D-amino acids and, at the same time, the target of D-serine nephrotoxicity.

Absorption↗
PubMed1992

Serine regulates phosphatidylethanolamine biosynthesis in the hamster heart.

The role of serine as a precursor and metabolic regulator for phosphatidylethanolamine biosynthesis in the hamster heart was investigated. Hearts were perfused with 50 microM [1-3H]ethanolamine in the presence or absence of serine for up to 60 min. Ethanolamine uptake was attenuated by 0.05-10 mM serine in a noncompetitive manner, and the incorporation of labeled ethanolamine into phosphatidylethanolamine was also inhibited by serine. Analysis of the ethanolamine-containing metabolites in the CDP-ethanolamine pathway revealed that the conversion of ethanolamine to phosphoethanolamine was reduced. The reduction was a result of an inhibition of ethanolamine kinase activity by an elevated pool of intracellular serine. Perfusion of the heart with 1 mM serine caused a 5-fold increase in intracellular serine pool. In order to examine the action of serine on other phosphatidylethanolamine metabolic pathways, hearts were perfused with [1-3H]glycerol in the presence and absence of serine. Serine did not cause any enhancement of phosphatidylethanolamine hydrolysis. The base-exchange reaction for phosphatidylserine formation or the decarboxylation of phosphatidylserine was not affected by serine perfusion. We conclude that circulating serine plays an important role in the modulation of phosphatidylethanolamine biosynthesis via the CDP-ethanolamine pathway in the hamster heart but does not affect the contribution of the decarboxylase pathway for phosphatidylethanolamine formation.

Animals↗
PubMed2004

D-Serine as a putative glial neurotransmitter.

Abundant recent evidence favors a neurotransmitter/neuromodulator role for D-serine. D-serine is synthesized from L-serine by serine racemase in astrocytic glia that ensheath synapses, especially in regions of the brain that are enriched in NMDA-glutamate receptors. D-serine is more potent than glycine at activating the 'glycine' site of these receptors. Moreover, selective degradation of D-serine but not glycine by D-amino acid oxidase markedly reduces NMDA neurotransmission. D-serine appears to be released physiologically in response to activation by glutamate of AMPA-glutamate receptors on D-serine-containing glia. This causes glutamate-receptor-interacting protein, which binds serine racemase, to stimulate enzyme activity and D-serine release. Thus, glutamate triggers the release of D-serine so that the two amino acids can act together on postsynaptic NMDA receptors. D-serine also plays a role in neural development, being released from Bergmann glia to chemokinetically enhance the migration of granule cell cerebellar neurons from the external to the internal granular layer.

Journal Article↗
PubMed2005

Comprehensive density functional theory study on serine and related ions in gas phase: conformations, gas phase basicities, and acidities.

Density functional theory (DFT) calculations have been performed to investigate the gas-phase conformations of serine and its three related ions (serineH(+), serine(-), and serine(2-)). The full ensemble of possible conformations, 324 conformations for serine, 108 for serineH(+), 162 for serine(-) and 54 for serine(2-), were first surveyed at B3LYP/6-31G level, and then the obtained unique conformations were further refined at B3LYP/6-311+G level. From full optimizations, 74 unique conformations for seine, 14 for serineH(+), 11 for serine(-), and 4 for serine(2-) were located, and their relative energies were also determined at B3LYP/6-311+G level. Atoms in molecules (AIM) analysis was carried out to establish rigorous definition of hydrogen bonds. Six types of intramolecular H-bonds in conformers of serine, six types in serineH(+), three types in serine(-), and two types in serine(2-) were identified within the framework of AIM theory and their relative strengths were determined based on topological properties at bond critical points (BCPs) of H-bonds. The intramolecular H-bonds were demonstrated to play an important role in deciding the relative stability of conformations of amino acids and the related ions. The enthalpies and Gibbs free energies of protonation and deprotonation reactions of serine and its related ions were calculated at B3LYP/6-311+G//B3LYP/6-31G, and B3LYP/6-311+G//B3LYP/6-311+G level. The calculated results are both in excellent agreement with the experimental data. We demonstrate in this study that B3LYP is an efficient and accurate method to predict the thermochemical and structural parameters of amino acids and the related ions.

Journal Article↗
PubMed1981

Growth Inhibition of Streptomyces Species by l-Serine and Its Effect on Tetracycline Biosynthesis.

The addition of serine to minimal medium inhibited the growth of Streptomyces aureofaciens and Streptomyces rimosus. Both the outgrowth of spores and the growth of vegetative cells were inhibited by l-serine. This effect was independent of the carbon source used. In rich nutrient medium, however, the serine effect was not observed. The presence of glycine and methionine in minimal medium reversed the growth inhibition imposed by serine, suggesting that a metabolic block related to the synthesis of these two amino acids was involved. A serine-tolerant mutant of S. aureofaciens isolated after ultraviolet irradiation showed a level of serine deaminase comparable to that of the wild-type strain, which indicated that tolerance to serine was not due to the presence of a more active deaminating enzyme in the mutant. Serine markedly reduced tetracycline and oxytetracycline biosynthesis with the parental strains of Streptomyces spp. The serine-tolerant mutant, however, produced almost the same amount of tetracycline in the presence or absence of serine. The final cell population in fermentation broth was not significantly reduced by l-serine, and the addition of glycine and methionine did not increase the tetracycline yields, which suggested that l-serine inhibition of antibiotic biosynthesis was by a mechanism different from that related to growth inhibition.

Journal Article↗
PubMed1985

Enzymes of serine metabolism in normal and neoplastic rat tissues.

Enzymes involved in the pathway of de novo serine biosynthesis (L-phosphoserine aminotransferase) and in alternative pathways of serine utilization (L-serine hydroxymethyltransferase, L-serine dehydratase and L-serine aminotransferase) were assayed in normal adult and fetal rat tissues and in a range of transplantable rat tumors. Serine dehydratase and serine aminotransferase activities were essentially confined to normal adult liver and kidney, whereas phosphoserine aminotransferase and serine hydroxymethyltransferase activities showed a more ubiquitous tissue distribution. In particular, phosphoserine aminotransferase and serine hydroxymethyltransferase activities were appreciable in neoplastic tissues, in the absence of the other enzymes of serine utilization. The pattern of enzyme distribution suggests that the synthesis of serine de novo is metabolically coupled to its utilization for nucleotide biosynthesis in tumors of differing tissue origins.

Animals↗
PubMed2006

A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia.

Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) D-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and D-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in D-serine levels and D/L-serine ratio in CSF of schizophrenia patients, while parietal-cortex D-serine was unaltered. Levels of L-serine, L-glutamine and L-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/D-amino acid oxidase ratio (34%) were reduced. Hippocampal D-amino-acid-oxidase protein levels significantly correlated with duration of illness (r=0.6, p=0.019) but not age. D-amino acid oxidase levels in patients with DOI>20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated D-amino acid oxidase protein levels may contribute to the lower CSF D-serine levels in schizophrenia.

Adolescent↗
PubMed2002

Neurobiology through the looking-glass: D-serine as a new glial-derived transmitter.

D-Amino acids have been known to be present in bacteria for more than 50 years, but only recently they were identified in mammals. The occurrence of D-amino acids in mammals challenge classic concepts in biology in which only L-amino acids would be present or thought to play important roles. Recent discoveries uncovered a role of endogenous D-serine as a putative glial-derived transmitter that regulates glutamatergic neurotransmission in mammalian brain. Free D-serine levels in the brain are about one third of L-serine values and its extracellular concentration is higher than many common L-amino acids. D-Serine occurs in protoplasmic astrocytes, a class of glial cells that ensheath the synapses and modulate neuronal activity. Biochemical and electrophysiological studies suggest that endogenous D-serine is a physiological modulator at the co-agonist site of NMDA-type of glutamate receptors. We previously showed that D-serine is synthesized by a glial serine racemase, a novel enzyme converting L- to D-serine in mammalian brain. The enzyme requires pyridoxal 5'-phosphate and it was the first racemase to be cloned from eucaryotes. Inhibitors of serine racemase have therapeutic implications for pathological processes in which over-stimulation of NMDA receptors takes place, such as stroke and neurodegenerative diseases. Here, we review the role of endogenous D-serine in modulating NMDA neurotransmission, its biosynthetic apparatus and the potential usefulness of serine racemase inhibitors as a novel neuroprotective strategy to decrease glutamate/NMDA excitotoxicity.

Animals↗
PubMed1988

Two systems in vitro that show insulin-stimulated serine kinase activity towards the insulin receptor.

Two systems in vitro are described that show insulin-stimulated phosphorylation of the insulin receptor on serine residues. In the first system, insulin receptor was purified partially from Fao rat hepatoma cells by direct solubilization of the cells in Triton X-100 and chromatography on wheat-germ-agglutinin-agarose. Phosphorylation of these preparations with [gamma-32P]ATP in the presence or absence of insulin resulted in 32P incorporation exclusively into phosphotyrosine residues. Serine kinase activity towards the insulin receptor was reconstituted by adding extracts of Fao cells. Prior exposure of the cells to insulin stimulated serine kinase activity towards the insulin receptor in extracts 7.2-fold. A receptor serine kinase activity enhanced by treatment of cells with cyclic AMP analogues was also retained in the reconstituted system. In the second system, insulin receptor and insulin-sensitive serine kinase activity towards the insulin receptor were co-purified from human placenta. The protocol involved preparation of membranes, before solubilization and chromatography on wheat-germ-agglutinin-agarose, by using gentle procedures designed not to disrupt a potentially labile association between the insulin receptor and the serine kinase. Serine kinase activity in these preparations towards the insulin receptor was stimulated up to 10-fold by insulin, and the stoicheiometry of serine phosphorylation was estimated to be approx 0.8 mol/mol of insulin receptor for phosphorylations performed in the presence of insulin. Thus a preparation of insulin receptor is described for the first time that is phosphorylated to high stoicheiometry on serine in an insulin-dependent manner. Conditions that facilitate recovery and assay of serine kinase activity are defined and discussed. These systems provide a basis for characterizing the nature of the insulin-sensitive serine kinase that phosphorylates the insulin receptor, and defining its role in insulin action and control of receptor function.

Animals↗
PubMed2001

Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3.

Upon exposure of cells to hydrogen peroxide (H(2)O(2)) phosphorylation of p53 was rapidly induced in human fibroblast GM00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, H(2)O(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Induction of phosphorylation of p53 on multiple serine residues by H(2)O(2) was caffeine-sensitive and blocked in ATM(-/-) cells. Polo-like kinase-3 (Plk3) activity was also activated upon H(2)O(2) treatment, and this activation was ATM-dependent. Recombinant His(6)-Plk3 phosphorylated glutathione S-transferase (GST)-p53 fusion protein but not GST alone. When phoshorylated in vitro by His(6)-Plk3, but not by the kinase-defective mutant His6-Plk3(K52R), GST-p53 was recognized by an antibody specifically to serine 20-phosphorylated p53, indicating that serine 20 is an in vitro target of Plk3. Also serine 20-phosphorylated p53 was coimmunoprecipitated with Plk3 in cells treated with H(2)O(2). Furthermore, although H(2)O(2) strongly induced serine 15 phosphorylation of p53, it failed to induce serine 20 phosphorylation in Plk3-dificient Daudi cells. Ectopic expression of a Plk3 dominant negative mutant, Plk3(K52R), in GM00637 cells suppressed H(2)O(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by Plk3.

Cell Cycle Proteins↗
PubMed2005

Metabolic engineering of Corynebacterium glutamicum for L-serine production.

Although L-serine proceeds in just three steps from the glycolytic intermediate 3-phosphoglycerate, and as much as 8% of the carbon assimilated from glucose is directed via L-serine formation, previous attempts to obtain a strain producing L-serine from glucose have not been successful. We functionally identified the genes serC and serB from Corynebacterium glutamicum, coding for phosphoserine aminotransferase and phosphoserine phosphatase, respectively. The overexpression of these genes, together with the third biosynthetic serA gene, serA(delta197), encoding an L-serine-insensitive 3-phosphoglycerate dehydrogenase, yielded only traces of L-serine, as did the overexpression of these genes in a strain with the L-serine dehydratase gene sdaA deleted. However, reduced expression of the serine hydroxymethyltransferase gene glyA, in combination with the overexpression of serA(delta197), serC, and serB, resulted in a transient accumulation of up to 16 mM L-serine in the culture medium. When sdaA was also deleted, the resulting strain, C. glutamicum delta sdaA::pK18mobglyA'(pEC-T18mob2serA(delta197)CB), accumulated up to 86 mM L-serine with a maximal specific productivity of 1.2 mmol h(-1) g (dry weight)(-1). This illustrates a high rate of L-serine formation and also utilization in the C. glutamicum wild type. Therefore, metabolic engineering of L-serine production from glucose can be achieved only by addressing the apparent key position of this amino acid in the central metabolism.

Corynebacterium glutamicum↗
PubMed1970

Physiological comparison of L-serine dehydratase and tryptophanase from Bacillus alvei.

Tryptophanase from Bacillus alvei also possesses serine dehydratase activity. A comparison of this enzyme with l-serine dehydratase [l-serine hydro-lyase (deaminating), EC 4.2.1.13] in toluene-treated whole cell preparations of the organism was undertaken. Tryptophanase is a constitutive enzyme in B. alvei. The dehydratase undergoes a repression-derepression-repression sequence as the l-serine level in the growth medium is increased from 0 to 0.1 m. Tryptophanase activity is decreased in organisms grown in medium containing glucose. Both enzymes are repressed in organisms grown in glycerol-containing medium. l-Serine dehydratase has a pH optimum of 7.5 in potassium phosphate buffer; tryptophanase functions optimally in this buffer at pH 8.2. Both enzymes lose activity in the presence of tris(hydroxymethyl)aminomethane buffer. Either K(+) or NH(4) (+) is required for full tryptophanase activity, but Na(+) is markedly inhibitory. These three cations are stimulatory to l-serine dehydratase activity. Both enzymes are subject to apparent substrate inhibition at high concentrations of their respective amino acids, but the inhibition of tryptophanase activity can be completely overcome by the removal of indole as it is formed. The dehydratase does not catalyze cleavage of d-serine, l-threonine, or alpha-substituted serine analogues at the concentrations tested. However, activity of the enzyme in cleaving l-serine is competitively inhibited by d-serine, indicating that the d-isomer can occupy an active site on the enzyme. The enzyme catalyzes cleavage of some beta-substituted serine analogues.

Ammonia↗
PubMed2004

Serine racemase expression in mouse cerebral cortex after permanent focal cerebral ischemia.

AIM: To study the alterations of the expressions of serine racemase in C57BL/6 mouse brain after permanent focal cerebral ischemia. METHODS: The mRNA level and the protein level of serine racemase were assayed by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. The amount of D-serine and L-serine were measured by HPLC. RESULTS: High levels of serine racemase were constitutively expressed in the normal cortex of mouse. At early stage after middle cerebral artery occlusion (MCAO), no significant change in expression of serine racemase was observed in temporoparietal cortex in ipsilateral hemisphere. However, delayed transient decreases of serine racemase in both mRNA and protein levels were detected from d 6 to d 10 after ischemia. Correspondingly, D-serine concentration also declined in the ipsilateral cortex during this period when compared with the D-serine level in the contralateral cortex. CONCLUSION: Delayed decreases in serine racemase expression and D-serine level occurred in the temporoparietal cortex at the late stage after focal cerebral ischemia.

Animals↗
PubMed2006

Measuring D-serine efflux from mouse cortical brain slices using online microdialysis-capillary electrophoresis.

Efflux of a number of important neurochemicals, including D-serine, L-serine, taurine, glutamate, and gamma-aminobutyric acid (GABA), from mouse cortical brain slices housed in a 7 microL perfusion chamber was monitored using online microdialysis-CE (MD-CE). Analyte concentrations could be measured every 20-27 s using the MD-CE instrument. Stimulation with high potassium induced increased release of D-serine. Kainic acid (KA) induced D-serine release, but this release was not blocked by 6-cyano-7-nitroquinoxaline-2,3-dione, suggesting that alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid/KA receptors do not mediate D-serine release. Application of L-serine, the precursor of D-serine, resulted in increased extracellular D-serine concentrations. L-Cysteine also increased extracellular D-serine levels in a partially Na+-dependent manner. The observed effects upon application of L-serine and L-cysteine support the involvement of ASC neutral amino acid transporters in regulating the extracellular concentration of D-serine concentration through competitive inhibition of uptake or increased release through heteroexchange.

Animals↗