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PubMed1989

Tissue localization of the carcinogenic glutamic acid pyrolysis product Glu-P-1 in control and beta-naphthoflavone-treated mice and rats.

Autoradiograms obtained after i.v. injection of the 14C-labelled carcinogenic glutamic acid pyrolysis product Glu-P-1 to mice and rats showed a pronounced uptake of radioactivity in the liver, kidney, thyroid and nasal mucosa. High concentrations of radioactivity were present in the bile and intestinal contents at short post-injection times. In the male rat, the Zymbal's gland and the preputial gland were identified as sites of high and specific binding at all post-injection times examined. The liver and nasal mucosa were identified as sites of retention of non-extractable radioactivity. In the pigmented mouse, Glu-P-1 and/or its metabolites were accumulated in melanin. Glu-P-1 is known to be activated by cytochrome P-448. Pretreatment with beta-naphthoflavone (a cytochrome P-448 inducer) did not change the tissue localization of radioactivity in either species except for the liver where the overall labelling was decreased. Neither did pretreatment of mice with the glutathione-depleting agent phorone change the distribution pattern significantly. However, combined pretreatments of mice with either phorone or beta-naphthoflavone and the cytochrome P-448 inhibitor 9-hydroxyellipticine resulted in an increased overall retention of radioactivity in the body.

Animals↗
PubMed1996

Islet cell and glutamic acid decarboxylase antibodies and heat-shock protein 65 responses in children with newly diagnosed insulin-dependent diabetes mellitus.

Islet cell antibodies (ICA) were detected in 66% and glutamic acid decarboxylase (GAD) antibodies in 64% of children (n = 47) with newly diagnosed insulin-dependent diabetes mellitus (IDDM). Fifteen percent of the patients had neither GAD nor ICA antibodies. Responses to mycobacterial heat-shock protein 65 (Hsp65) were detected in all patients. There was a significant correlation between anti-GAD antibodies and proliferation of peripheral blood mononuclear cells to Hsp65, and between ICA and antibodies to Hsp65.

Adolescent↗
PubMed1993

Many spinal cord cells transiently express low molecular weight forms of glutamic acid decarboxylase during embryonic development.

At early developmental stages in the rat spinal cord (embryonic day 13), when neuronal progenitors are still proliferating, most differentiating neurons express truncated forms of glutamic acid decarboxylase (GAD) (approximately 25 kDa) which are the products of alternative splicing of the GAD67 gene. These truncated proteins do not appear to synthesize gamma-aminobutyric acid (GABA). The amino acid is detected in cells only after alternative splicing of the GAD67 gene generates a full-length, 67 kDa enzymatically active form of GAD. Both the 67 kDa GAD and GABA colocalize and appear diffusely distributed in the cytoplasm of embryonic neurons. GABA does not appear associated with synaptic vesicles until after birth, when its intracellular distribution becomes punctate and it colocalizes with synaptophysin. At this time, it also colocalizes with an immunologically distinct 65 kDa GAD protein encoded by a second GAD gene (GAD65). Expression of different GAD-related proteins with distinct intracellular distributions during development suggests that GABA, the product of these enzymes, may have trophic or metabolic roles during spinal cord differentiation.

Animals↗
PubMed1991

Differential effects of monocular deprivation on glutamic acid decarboxylase and type II calcium-calmodulin-dependent protein kinase gene expression in the adult monkey visual cortex.

Increases in immunocytochemically detectable type II calcium-calmodulin-dependent protein kinase (CaM II kinase) and decreases in immunocytochemically detectable glutamic acid decarboxylase (GAD) are known to occur in the visual cortex of adult monkeys following brief periods of monocular visual deprivation. In the present study, GAD and CaM II kinase gene expression was investigated under these conditions. The polymerase chain reaction (PCR) was used to generate species-specific cDNA clones that were used to make antisense RNA probes. A second form of CaM II kinase alpha, CaM II kinase alpha-33, which contains an additional phosphorylation consensus sequence, was identified. In situ hybridization in normal visual cortex revealed a complex sublaminar organization of GAD-expressing cells within layers IVC and VI and a distribution of CaM II kinase alpha-expressing cells that was greatest in layers II, III, IVB, and VI. In situ hybridization in the cortex from animals that had been monocularly deprived revealed enhanced CaM II kinase mRNA levels in deprived-eye columns of layer IVC and, associated with the deprived eye, cytochrome oxidase-stained periodicities in other layers. In layer IV, the enhancement of labeling in deprived-eye stripes was, on average, 16% greater than in normal-eye stripes. By contrast, GAD, mRNA levels appeared unchanged in all layers, suggesting a posttranscriptional regulatory mechanism.

Amino Acid Sequence↗
PubMed1984

Characterization of a glutamic acid neurotransmitter binding site on neuroblastoma hybrid cells.

Glutamate is thought to be a major excitatory neurotransmitter in the central nervous system. To study the glutamate receptor and its regulation under carefully controlled conditions, the specific binding of [3H]glutamate was characterized in washed membranes isolated from a neuroblastoma X retina hybrid cell line, N18-RE-105. [3H]Glutamate bound in a saturable and reversible fashion with an apparent dissociation constant, KD, of 650 nM and a maximum binding capacity, Bmax, of 16 pmol/mg of protein. Pharmacologic characterization of the site indicates that it closely resembles the Na+-independent binding site for glutamate found on brain membranes and thought to be an excitatory amino acid neurotransmitter receptor. Thus, while kainate, N-methyl-DL-aspartate, and nonamino acid ligands did not displace [3H]glutamate, quisqualate and ibotenate were potent inhibitors of specific binding. Furthermore, this binding site is regulated by ions in a manner which resembles that described in the hippocampus (Baudry, M., and Lynch, G. (1979) Nature (Lond.) 282, 748-750). Calcium (10 mM) increased the number of binding sites 2.6-fold with no change in receptor-ligand affinity. Lanthanum (1 mM) was the only other cation added which enhanced (3-fold) the binding of [3H]glutamate. Monovalent cations resulted in a decrease in the number of glutamate binding sites. Incubation of membranes in the presence of chloride ions caused a marked increased in [3H] glutamate binding, an effect which was synergistic with that of calcium incubation. Thus, N18-RE-105 cells possess a binding site for [3H]glutamate pharmacologically similar to an excitatory neurotransmitter binding site in brain and which exhibits regulatory properties resembling those previously described in hippocampal membranes, providing an excellent model for mechanistic studies.

Animals↗
PubMed2002

Absence of long-term depression in the visual cortex of glutamic Acid decarboxylase-65 knock-out mice.

Long-term depression (LTD) is widely considered a mechanism for experience-induced synaptic weakening in the brain. Recent in vivo studies on glutamic acid decarboxylase [GAD 65 (-/-)] knock-out mice indicates that GABAergic synaptic inhibition is also required for the normal weakening of deprived inputs in the visual cortex. To better understand how GABAergic inhibition might control plasticity, we assessed the status of synaptic inhibition and LTD in visual cortical slices of GAD 65 knock-out mice. We found the following: (1) the efficacy of GABAergic synapses during repetitive activation is reduced in GAD 65 (-/-) mice; (2) the induction of LTD is impaired in the visual cortex of GAD 65 (-/-) mice; and (3) chronic, but not acute, treatment with the benzodiazepine agonist diazepam restores LTD in GAD 65 (-/-) mice. These results suggest that a certain inhibitory tone is required for the induction of LTD in visual cortex. We propose that the lack of visual cortical LTD in GAD 65 (-/-) may account for the lack of experience-dependent plasticity in these mice.

Animals↗
PubMed1976

Synthesis and chemical behaviour of D-glucosyl esters of glutamic acid having the side-chain carboxyl group involved in the glycosidic linkage.

Simultaneous and stepwise deprotection of the fully benzylated D-glucosyl esters of 1-benzyl N-benzyloxycarbonyl- and N-tert-butyloxycarbonyl-L-glutamic acid (1 and 5, respectively) have been examined. Catalytic hydrogenation of 1 led to intramolecular aminolysis to give pyroglutamic acid and D-glucose, but similar treatment in the presence of trifluoroacetic acid afforded both anomers of 1-O-(L-gamma-glutamyl)-D-glucopyranose, which were characterized as trifluoroacetates (2alpha and 2beta) and converted into 2,3,4,6-tetra-O-acetyl-1-O-[1-methyl N-(acetyl)-L-glutam-5-oyl]-D-glucopyranose (4) which was also prepared by a definitive method. Hydrogenolysis of 5 gave both anomers of 1-O-[N-(tert-butyloxycarbonyl)-L-gamma-glutamyl]-D-glucopyranose (6), which, upon treatment with trifluoroacetic acid at - 10 degrees, afforded 2alpha and 2beta, respectively. The structure of 6beta was established by its conversion into 2,3,4,6-tetra-O-acetyl-1-O-[1-methyl N-(tert-butyloxycarbonyl)-L-glutam-5-oyl]-beta-D-glucopyranose (7beta), whereas similar treatment of 6alpha gave a mixture of 1,3,4,6-tetra-O-acetyl-2-O-[1-methyl N-(tert-butyloxycarbonyl)-L-glutam-5-oyl]-alpha-D-glucopyranose (9) and 7alpha. A 1 leads to 2 acyl migration occurred during esterification of the aglycon carboxyl group of 6alpha with diazomethane to give 2-O-[1-methyl N-(tert-butyloxycarbonyl)-L-glutam-5-oyl]-alpha-D-glucopyranose (8).

Chemical Phenomena↗
PubMed1985

Colocalization of [3H]muscimol and antisera to GABA and glutamic acid decarboxylase within the same neurons in monkey retina.

Two procedures have been used to test for the colocalization of different neuroanatomical gamma-aminobutyric acid (GABA)ergic markers within the same neurons in primate retina. First, sequential immunocytochemical processing of sections was done using antisera to glutamic acid decarboxylase and to GABA, and these antisera were visualized by peroxidase-antiperoxidase and fluorescein isothiocyanate techniques respectively. Colocalization of both antisera was found within the same neuron cell bodies. In the second experiment, immunocytochemical staining using GABA antiserum was performed on retinal tissue that had been previously incubated in vitro for neuronal uptake of [3H]muscimol. Both markers colocalized in 70% of the labeled cell body population.

Animals↗
PubMed1993

Baculovirus-mediated expression of human 65 kDa and 67 kDa glutamic acid decarboxylases in SF9 insect cells and their relevance in diagnosis of insulin-dependent diabetes mellitus.

cDNAs coding for the full-length human 65 and 67 kDa glutamic acid decarboxylases (GAD65 and GAD67) were amplified from pancreas and hippocampus cDNA libraries by polymerase chain reaction, respectively. Both cDNAs were inserted into a baculovirus vector which mediated highly efficient expression of the human GAD65 and GAD67 with histidine-hexapeptides as affinity ligands at their C-termini in Spodoptera frugiperda (Sf9) cells. The recombinant GAD proteins were purified to homogeneity by affinity chromatography using a metal-chelating matrix. The infected Sf9 insect cells expressed the recombinant human GAD65 and GAD67 with natural-like conformations, as confirmed by measurement of their enzyme activities as well as their fully restored autoantigenicities. Immunoprecipitation of metabolically labeled infected Sf9 cells demonstrated the autoantigenic potential of the recombinant GAD proteins. The practicability of using recombinant GAD65 and GAD67 derived from the baculovirus expression system for the development of an immunoassay for the diagnosis of insulin-dependent diabetes mellitus is discussed.

Animals↗
PubMed1992

A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase.

N-[4-[2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid (15), prepared in five steps from 2-pivaloyl-7-deazaguanine, has been found to be an antitumor agent with its primary site of action at thymidylate synthase rather than purine synthesis. This compound appears to be a promising candidate for clinical evaluation.

Animals↗
PubMed1992

Differential effects of insulin on choline acetyltransferase and glutamic acid decarboxylase activities in neuron-rich striatal cultures.

We studied the effects of insulin, nerve growth factor (NGF), and tetrodotoxin (TTX) on cellular metabolism and the activity of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) in neuron-rich cultures prepared from embryonic day 15 rat striatum. Insulin (5 micrograms/ml) increased glucose utilization, protein synthesis, and GAD activity in cultures plated over a range of cell densities (2,800-8,400 cells/mm2). TTX reduced GAD activity; NGF had no effect on GAD activity. Insulin treatment reversibly reduced ChAT activity in cultures plated at densities of greater than 4,000 cells/mm2, and the extent of this reduction increased with increasing cell density. The number of acetylcholinesterase-positive neurons was not reduced by insulin, suggesting that insulin acts by down-regulating ChAT rather than by killing cholinergic neurons. Insulin-like growth factor-1 (IGF-1) reduced ChAT activity at concentrations 10-fold lower than insulin, suggesting that insulin's effect on ChAT may involve the IGF-1 receptor. NGF increased ChAT activity; TTX had no effect on ChAT activity. These results suggest that striatal cholinergic and GABAergic neurons are subject to differential trophic control.

Animals↗
PubMed2003

Aggregation behaviors and their pH sensitivity of cholesterol-conjugated proteinoids composed of glutamic acid and aspartic acid matrix.

Cholesterol-conjugated proteinoids and their aggregation behaviors were investigated with model proteinoid systems. Model proteinoids of molecular weights in the range of 4000 to 6000 were synthesized by anhydrous thermal condensation forming a matrix with glutamic acid and aspartic acid and of naturally occurring amino acids. Nuclear magnetic resonance and Fourier transform infrared spectra suggested that cholesterol was conjugated to carboxyl group-forming pendants. Native water-soluble proteinoids can form microspheres in acidified or heated conditions, but the cholesterol-conjugated proteinoids were found to form aggregates in water, regardless of the temperature or pH of the solutions. The hydrophobic pendant moieties come to a compact association in core, whereas the hydrophilic chains provide a shield layer.

Aspartic Acid↗
PubMed1994

Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease.

We have done a study designed to ascertain the effectiveness of measuring antibodies to glutamic acid decarboxylase (anti-GAD) in predicting insulin-dependent diabetes mellitus (IDDM). Anti-GAD was measured in prediabetic sera from 151 women aged 20-39 years with newly diagnosed diabetes mellitus who had been identified through a nationwide diabetes register. Multiple serum samples had been collected from these women up to 10 years before the clinical onset of diabetes during their earlier pregnancies. Anti-GAD was measured with a radioimmunoprecipitation assay. Anti-GAD was detected in 82% of 28 women with IDDM, in 36% of 11 women with non-insulin-dependent diabetes mellitus, and in 5% of 112 women with gestational diabetes mellitus. In a random sample of 100 non-diabetic young Finnish women, none had anti-GAD. The sensitivity of the anti-GAD assay for predicting IDDM was 82.1% and the specificity was 100%. The longest time of anti-GAD positivity before clinical onset of IDDM was 10 years. Once positive, anti-GAD levels remained stable and no patients became negative after a positive test during the prediabetic period. Anti-GAD is a valuable early predictive marker and is associated with a very high risk for development of IDDM.

Adult↗
PubMed1988

Catecholaminergic innervation of luteinizing hormone-releasing hormone and glutamic acid decarboxylase immunopositive neurons in the rat medial preoptic area. An electron-microscopic double immunostaining and degeneration study.

Catecholaminergic innervation of luteinizing hormone-releasing hormone (LHRH) and glutamic acid decarboxylase (GAD) immunoreactive neurons in the rat medial preoptic area (MPO) was studied using electron-microscopic (EM) double-label immunostaining and combinations of single- and double-label immunostaining with acute axonal degeneration. The EM double-immunostaining experiments included double staining for either tyrosine hydroxylase (TH) and LHRH, or TH and GAD. Analysis of TH and LHRH double-immunostained material revealed synaptic connections between TH immunoreactive axons and LHRH immunopositive neurons. The TH and GAD double-staining experiments also demonstrated synaptic connections between axons immunoreactive for TH and GAD immunopositive neurons. Two days following unilateral surgical transection of the ventral and dorsal noradrenergic bundles, synaptic connections were found between degenerated boutons and GAD immunoreactive neurons in the ipsilateral MPO. However, no synapses could be observed in the same area between degenerated axons and the LHRH immunopositive neurons. Following the same operation and immunostaining for TH, a moderate number of degenerating TH axons as well as a large number of nondegenerated TH immunoreactive boutons were observed. Double immunostaining for TH and GAD in MPO sections ipsilateral to the operation revealed synaptic connections between the degenerating TH immunopositive axons and GAD immunoreactive neurons. These results suggest that there are direct synaptic connections between catecholaminergic axons and GAD and LHRH immunoreactive neurons in the medial preoptic area of the rat. Some of the connections between TH immunopositive afferents and GAD immunoreactive neurons may represent connections from noradrenergic neurons in the brain stem, while the majority of TH-GAD and TH-LHRH connections may represent innervation of GABA and LHRH neurons from local dopamine-containing cells.

Adrenergic Fibers↗
PubMedDate not supplied

Poly-l-glutamic acid derivatives as multifunctional vectors for gene delivery. Part A. Synthesis and physicochemical evaluation.

This paper describes the synthesis and evaluation of a series of multifunctional poly-l-glutamic acid derivatives that can be used as vectors for gene delivery. They readily form polyelectrolyte complexes with DNA, resulting in a reduced surface charge and size of the DNA. The formation of a polymer-DNA complex and the stability toward serum albumin was analyzed by ethidium bromide fluorescence measurements and agarose gel retardation studies. Most polymers, except those with more than 80% imidazoles, are able to condense calf thymus DNA, thus forming complexes with sizes varying between 105 and 172 nm. The surface charge of the complexes was determined at different charge ratios by zeta potential measurements. The buffering properties of the polymers were determined via titration studies. The results show that the polymers are able to buffer the endosomal environment, although to a smaller extent than polyethyleneimine. The first part of this study is devoted to the synthesis and the physicochemical evaluation of the multifunctional polymers and their use as carriers for genetic information. The second part, to be published subsequently, discusses the biological evaluation of the polymers and their complexes with DNA.

Biocompatible Materials↗