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At least 181 records · Page 10Linked to original sources
PubMed1998

Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome.

Stiff-man syndrome (SMS) is a rare disorder of the central nervous system thought to result from an impairment of gamma-aminobutyric acid (GABA)ergic neurotransmission. Autoantibodies to the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), present in about 60% of SMS patients, have suggested an autoimmune pathogenesis of SMS. By using serum or cerebrospinal fluid from 25 SMS patients, we assessed the effect of GAD autoantibodies (GAD-A) on GAD enzymatic activity in vitro; 83% of GAD-A-positive SMS sera reduced GABA production in crude rat cerebellar extracts, whereas GAD-A- sera from SMS patients or healthy blood donors did not alter the enzyme activity. Inhibition of GABA synthesis by SMS sera was dose dependent and mediated by the purified IgG fraction of the sera. Human monoclonal GAD65-A and IgG purified from serum of GAD-A-positive patients with insulin-dependent diabetes or autoimmune polyendocrine syndrome did not affect GAD activity, suggesting that a specific epitope recognition of GAD-A mediates inhibition of GAD. The disease-specific detection of GAD-inhibitory antibodies is compatible with their functional involvement in the etiopathology of SMS; the relevance of such antibodies in vivo, however, remains to be determined.

Adult↗
PubMed1997

Cleft palate in mice with a targeted mutation in the gamma-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67.

The functions of neurotransmitters in fetal development are poorly understood. Genetic observations have suggested a role for the inhibitory amino acid neurotransmitter gamma-aminobutyric acid (GABA) in the normal development of the mouse palate. Mice homozygous for mutations in the beta-3 GABAA receptor subunit develop a cleft secondary palate. GABA, the ligand for this receptor, is synthesized by the enzyme glutamic acid decarboxylase. We have disrupted one of the two mouse Gad genes by gene targeting and also find defects in the formation of the palate. The striking similarity in phenotype between the receptor and ligand mutations clearly demonstrates a role for GABA signaling in normal palate development.

Animals↗
PubMed1997

Differential and time-dependent changes in gene expression for type II calcium/calmodulin-dependent protein kinase, 67 kDa glutamic acid decarboxylase, and glutamate receptor subunits in tetanus toxin-induced focal epilepsy.

To study potential molecular mechanisms of epileptogenesis in the neocortex, the motor cortex of rats was injected with tetanus toxin (TT), and gene expression for 67 kDa glutamic acid decarboxylase (GAD-67), type II calcium/calmodulin-dependent protein kinase (CaMKII), NMDA receptor subunit 1 (NR1), and AMPA receptor subunit 2 (GluR2) was investigated by in situ hybridization histochemistry. Injections of 20-35 ng TT induced recurrent seizures after a postoperative period ranging from 4 to 13 d. A majority of rats perfused 5-7 d after TT injection showed altered gene expression, but the changes varied in their areal extent, ranging from most neocortical areas on the injected side in some rats to mainly the frontoparietal cortex or the motor cortex in others. Epileptic rats perfused 14 d after TT injection showed a focus of increased GAD-67 and NR1, and of decreased alpha-CaMKII and GluR2 mRNA levels at the injection site. A zone of cortex surrounding the focus showed changes in alpha-CaMKII, GAD-67, and NR1 mRNA levels that were reciprocal to those in the focus. The results suggest that TT-induced seizure activity initially spread to a variable extent but was gradually restricted 2-3 d after seizure onset. The focus and the surround showing reciprocal changes in gene expression are thought to correspond to the electrophysiologically identified epileptic focus and inhibitory surround, respectively. The findings suggest that lateral inhibition between neighboring cortical regions will be affected and contribute to a neurochemical segregation of an epileptic focus from surrounding cortex.

Animals↗
PubMed2006

Formation of pyroglutamic acid from N-terminal glutamic acid in immunoglobulin gamma antibodies.

The status of the N-terminus of proteins is important for amino acid sequencing by Edman degradation, protein identification by shotgun and top-down techniques, and to uncover biological functions, which may be associated with modifications. In this study, we investigated the pyroglutamic acid formation from N-terminal glutamic acid residues in recombinant monoclonal antibodies. Almost half the antibodies reported in the literature contain a glutamic acid residue at the N-terminus of the light or the heavy chain. Our reversed-phase high-performance liquid chromatography-mass spectrometry method could separate the pyroglutamic acid-containing light chains from the native light chains of reduced and alkylated recombinant monoclonal antibodies. Tryptic peptide mapping and tandem mass spectrometry of the reduced and alkylated proteins was used for the identification of the pyroglutamic acid. We identified the formation of pyroglutamic acid from N-terminal glutamic acid in the heavy chains and light chains of several antibodies, indicating that this nonenzymatic reaction does occur very commonly and can be detected after a few weeks of incubation at 37 and 45 degrees C. The rate of this reaction was measured in several aqueous buffers with different pH values, showing minimal formation of pyroglutamic acid at pH 6.2 and increased formation of pyroglutamic acid at pH 4 and pH 8. The half-life of the N-terminal glutamic acid was approximately 9 months in a pH 4.1 buffer at 45 degrees C. To our knowledge, we showed for the first time that glutamic acid residues located at the N-terminus of proteins undergo pyroglutamic acid formation in vitro.

Alkylation↗
PubMed1983

Glutamic acid decarboxylase in cerebrospinal fluid in infancy and childhood. Part I. Glutamic acid decarboxylase activity in cerebrospinal fluid of normal infants and children.

Glutamic acid decarboxylase (GAD) activity in the cerebrospinal fluid (CSF) of normal infants (n:14) and children (n:28) was determined by measuring the amount of 14CO2 released from L-[1-14C]-glutamic acid. The mean GAD activity in CSF of infants and children was 5.2 +/- 2.5 pmol CO2 formed/hr/ml. Dividing these subjects into 4 groups according to age, GAD activities in CSF were 5.4 +/- 1.6 pmol CO2 formed/hr/ml in neonates (0-1 m), 3.6 +/- 1.6 pmol CO2 formed/hr/ml in infants (2-12 m), 3.9 +/- 1.1 pmol CO2 formed/hr/ml in young children (2-6 yr) and 7.1 +/- 2.3 pmol CO2 formed/hr/ml in school children (7-16 yr), respectively. In neonates and school children, GAD activities were significantly higher (p less than 0.001) than those in the other age groups. In infants under 6 months of age, a significantly negative correlation between GAD activity in CSF and their ages was recognized (r = -0.52, p less than 0.001). In infants and children ranging from 6 months to 16 years of age, a significantly positive correlation between GAD activity in CSF and their ages was found (r = 0.67, p less than 0.001). These data suggest that high GAD activity in neonates may be due to hypoxia at birth and the activity gradually increases from 6 months to 15 years of age.

Adolescent↗
PubMed1995

Staphylococcus haemolyticus contains two D-glutamic acid biosynthetic activities, a glutamate racemase and a D-amino acid transaminase.

Two D-glutamic acid biosynthetic activities, glutamate racemase and D-amino acid transaminase, have been described previously for bacteria. To date, no bacterial species has been reported to possess both activities. Genetic complementation studies using Escherichia coli WM335, a D-glutamic acid auxotroph, and cloned chromosomal DNA fragments from Staphylococcus haemolyticus revealed two distinct DNA fragments containing open reading frames which, when present, allowed growth on medium without exogenous D-glutamic acid. Amino acid sequences of the two open reading frames derived from the DNA nucleotide sequences indicated extensive identity with the amino acid sequence of Pediococcus pentosaceous glutamate racemase in one case and with that of the D-amino acid transaminase of Bacillus spp. in the second case. Enzymatic assays of lysates of E. coli WM335 strains containing either the cloned staphylococcal racemase or transminase verified the identities of these activities. Subsequent DNA hybridization experiments indicated that Staphylococcus aureus, in addition to S. haemolyticus, contained homologous chromosomal DNA for each of these genes. These data suggest that S. haemolyticus, and probably S. aureus, contains genes for two D-glutamic acid biosynthetic activities, a glutamate racemase (dga gene) and a D-amino acid transaminase (dat gene).

Amino Acid Isomerases↗
PubMed1997

Chemical analysis of poly-gamma-glutamic acid produced by plasmid-free Bacillus subtilis (natto): Evidence that plasmids are not involved in poly-gamma-glutamic acid production.

It has been postulated that the psf gene on a small plasmid, pUH1 (5.8 kb), regulates positively the synthesis of capsular poly-gamma-glutamic acid (gammaPGA) in Bacillus subtilis (natto) Asahikawa. We found that this strain harbored a second plasmid, named pNAGL1 (ca. 50 kb), in addition to pUH1. The growth conditions that cure pUH1 or pNAGL1 were established. The plasmid-free NAF4 strain derived from B. subtilis (natto) Asahikawa was found to produce gammaPGA which was the same as the parent strain in terms of quantity and chemical properties having the same molecular mass and content of D-glutamic acid. Furthermore, as in the case of the parent cells, the D-glutamic acid in gammaPGA, which is known to increase up to ca. 80% of the total glutamic acid as Mn(2+) ion concentration increases in growth medium, was found to make up 80% of the total glutamic acid of the gammaPGA produced by NAF4 cells grown in the presence of 0.1 mm MnCl(2). Thus, these results led us to conclude that the plasmids do not encode any gene important for gammaPGA production.

Journal Article↗
PubMed1988

The actions of cyclopentane analogues of glutamic acid at binding sites for kainic and glutamic acids.

The actions of the four isomers of 1-amino-1, 3-cyclopentane dicarboxylate (ACPD), a conformationally restricted analogue of glutamate, have been examined for their ability to displace radiolabelled kainate and glutamate from their binding sites on membranes prepared from rat brain. All four of the isomers reduced specific kainate binding, and all enhanced that of glutamate although one (D-(-)-cis-(1R,3R)-ACPD) was significantly more active in this respect than were the other three. The results are discussed in terms of the pharmacological effects of the isomers of ACPD on single neurones and the possible structural requirements of the NMDA and kainate receptors.

Amino Acids↗
PubMed1998

Aspartic and glutamic acids increase in the frontal cortex during prostaglandin E1 hyperthermia.

The aim of the present experiment was to evaluate the role played by aspartic acid and glutamic acid of frontal cerebral cortex during the hyperthermia induced by prostaglandin E1. Two groups of six Sprague Dawley male rats were anaesthetized with ethyl-urethane. The frontal cortical concentrations of aspartic and glutamic acids, the firing rate of the sympathetic nerves to the interscapular brown adipose tissue, the colonic and interscapular brown adipose tissue temperatures were monitored both before and after an intracerebroventricular injection of prostaglandin E1 (500 ng) or saline. Aspartic and glutamic acids were collected using a microdialysis probe placed in the frontal cortex. Concentrations of aspartic and glutamic acids were measured by high-pressure liquid chromatography with fluorescence detector. Prostaglandin E1 induced an increase in the concentrations of aspartic and glutamic acids, in the firing rate of sympathetic nerves and in the colonic and interscapular brown adipose tissue temperatures. The findings of the present experiment indicate that an intracerebroventricular injection of prostaglandin E1 causes release of aspartic and glutamic acids in the frontal cortex.

Adipose Tissue, Brown↗
PubMed1984

Genetic control of major histocompatibility complex-linked immune responses to synthetic polypeptides in man: poly(L-phenylalanine, L-glutamic acid)-poly (DL-alanine)--poly(L-lysine) and L-glutamic acid, L-alanine, L-tyrosine (60:30:10).

Vigorous lymphoproliferative responses to synthetic polypeptides poly(L-phenylalanine, L-glutamic acid)-poly(DL-alanine)--poly(L-lysine) [( Phe,G)-A--L], and L-glutamic acid, L-alanine, L-tyrosine (60:30:10) (GAT) were observed in cells from 92 unrelated subjects. Thirty-three percent responded to (Phe,G)-A--L and 77% to GAT. No HLA association was observed with responses to these two antigens. Family studies indicated that two complementary immune response (Ir) genes are required for response to each antigen. Eleven matings were informative for linkage analysis between HLA and these Ir genes. Families in which the complementary genes are in coupling gave maximal lod scores (log of the odds) of 4.50 for (Phe,G)-A--L and 7.57 for GAT for 0 = 0. In a HLA-B/D recombinant family, the Ir- PheGAL genes are mapped towards the HLA-D region. The localization of Ir-GAT genes close to HLA-B was provided by a HLA-A/B recombinant.

Genes, MHC Class II↗
PubMed2005

Synthesis and pharmacological evaluation of side chain modified glutamic acid analogues of the neuroprotective agent glycyl-L-prolyl-L-glutamic acid (GPE).

The synthesis of eight GPE* analogues, wherein the gamma-carboxylic moiety of the glutamic residue has been modified, is described by coupling readily accessible N-benzyloxycarbonyl-glycyl-L-proline with various analogues of glutamic acid. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glutamate residue on the observed neuroprotective properties of the endogenous tripeptide GPE.

Animals↗
PubMed1991

[Comparison of central effects produced by intracerebral injection of glutamic acid, quisqualic acid, and kainic acid].

Icv glutamic acid (Glu), quisqualic acid (QA) and kainic acid (KA) significantly increased spontaneous activity of mice in photecell box, and induced dose-dependent rise of blood pressure in anesthetized rats. Their intensities were arranged in the order of KA greater than Glu greater than QA. In mice step-through test Glu 0.1 micrograms icv improved learning and memory; KA 1 ng had no evident effect; and QA 0.1 microgram impaired learning and memory, which were also confirmed by step-down test in normal mice. Therefore, the non-NMDA (N-methyl-D-aspartate) receptor subtype might be different from the NMDA receptor subtype in the action of learning and memory.

Animals↗
PubMed1998

A novel surgical glue composed of gelatin and N-hydroxysuccinimide activated poly(L-glutamic acid): Part 1. Synthesis of activated poly(L-glutamic acid) and its gelation with gelatin.

Although fibrin glue has been widely used as a surgical adhesive, its components, fibrinogen and thrombin, obtained from human blood are not completely free from the risk of virus infection due to acquired immune deficiency and hepatitis. Recently, we have reported that a polymer pair composed of gelatin and poly(L-glutamic acid) (PLGA) promptly forms a gel and can firmly bond to soft tissues when crosslinked with the aid of water-soluble carbodiimide (WSC). The present study was undertaken to design a new PLGA-gelatin glue without using WSC. Two kinds of PLGA with molecular weights of 71 and 22 kDa were employed to prepare N-hydroxysuccinimide (NHS) activated derivatives. The NHS-activated PLGA could be synthesized at high yields and was found to be stable for an extended time without losing the ability to crosslink with gelatin when stored under a dry-cold condition. This NHS-activated PLGA could spontaneously form a gel with gelatin in an aqueous solution within a short time, comparable to a commercial fibrin glue, when gelation was allowed to proceed at pH 8.3. The NHS-activated PLGA prepared from PLGA with the molecular weight of 22 kDa could be readily dissolved at high concentrations and its ability to form a gel was maintained for more than 10 min when an acidic 8% NHS-activated PLGA solution was used. The bonding strength of PLGA gelatin glues with natural tissue was higher than that of fibrin glue. These findings strongly suggest that this combination of gelatin and NHS-PLGA is very promising as a surgical adhesive and may possibly replace fibrin glues prepared from human blood components.

Animals↗