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PubMed2003

Effects of c-fos antisense oligodeoxynucleotide on 5-HT-induced upregulation of preprodynorphin, preproenkephalin, and glutamic acid decarboxylase mRNA expression in cultured rat spinal dorsal horn neurons.

Effects of c-fos antisense oligodeoxynucleotide (ASO) on serotonin (5-HT)-induced upregulation of preprodynorphin (ppDyn), preproenkephalin (ppEnk), and glutamic acid decarboxylase (GAD), a special chemical marker for gamma-aminobutyric acid (GABA) neurons, mRNAs in cultured spinal dorsal horn neurons were investigated in order to extend our understanding of expressions of opioid peptides and GABA in spinal cord regulated by the descending serotonergic efferents. Reverse transcription-polymerase chain reaction analysis revealed a time-course increase in the expression of mRNAs encoding c-fos, ppDyn, ppEnk, and GAD after administration of 5-HT (100 nM). Administration of c-fos ASO (0.02 nM) 30 min prior to 5-HT application markedly blocked the expression of c-fos gene. Moreover, c-fos ASO pretreatment significantly decreased the 5-HT-induced upregulation of ppDyn and ppEnk mRNAs, but failed to affect the expression level of GAD mRNA. These results suggest that the serotoningic raphe-spinal efferents might play an important role in regulating the synthesis of enkephalin, dynorphin, and GABA in the spinal dorsal horn neurons. The immediate early oncogene c-fos might be involved in the 5-HT-induced increase in ppDyn and ppEnk expression. However, under the present experimental conditions, c-fos does not seem to be associated with the upregulation of GAD mRNA induced by 5-HT.

Animals↗
PubMed2002

Role of the progesterone receptor in restrained glutamic acid decarboxylase gene expression in the hypothalamus during the preovulatory luteinizing hormone surge.

Previous work by our laboratory demonstrated that activation of the progesterone receptor through exogenous administration of progesterone suppressed glutamic acid decarboxylase-67 (GAD(67)) mRNA in the hypothalamus of the estrogen-primed ovariectomized rat. Since GAD(67) is the major synthetic enzyme for the inhibitory transmitter, gamma-aminobutyric acid, the finding raised the possibility that the endogenous activation of the progesterone receptor may act to restrain GAD(67) expression during the natural preovulatory gonadotropin surge during proestrus in the rat, thereby allowing GnRH secretion and the resultant LH surge. To test this hypothesis, the progesterone receptor antagonist, RU486, was administered to regularly cycling proestrous rats and the effect on GAD(67) and GAD(65) mRNA levels in the preoptic area (POA) and medial basal hypothalamus (MBH) was examined. Serum luteinizing hormone (LH) levels were also examined in order to identify correlations between changes in POA and MBH GAD levels and production of the LH surge. GAD(67) mRNA levels in the POA were increased in the cycling rat during proestrus at 18.00 h at the peak and just preceding the termination of the LH surge. There was no change in GAD(67) mRNA levels in the MBH, and GAD(65) expression was also unchanged during proestrus in the POA and MBH. Treatment with the antiprogestin RU486 resulted in an increase in GAD(67) mRNA levels at 12.00 and 14.00 h in the POA, and in the MBH at 14.00, 16.00, and 18.00 h during proestrus, effects which preceded and correlated with the attenuated LH surge in RU486-treated rats at 18.00 h. GAD(65) mRNA levels were also elevated by RU486 at 14.00 and 16.00 h in the POA, and at 14.00 h in the MBH during proestrus. These findings suggest that the progesterone receptor plays a role in restraining GAD expression in the hypothalamus during proestrus, and that this effect may be important for the production of the GnRH and LH surge.

Animals↗
PubMed1980

Effect of discrete kainic acid-induced lesions of corpus caudatus and globus pallidus on glutamic acid decarboxylase of rat substantia nigra.

Locally applied kainic acid was used in order to destroy pallidal perikarya without damaging axons en passage, in an effort to clarify the role of the globus pallidus as a source of nigral GABAergic terminals. Rats were microinjected unilaterally with kainic acid in the globus pallidus, head, body and tail of the caudate and were sacrificed 7 days later. The forebrain of each rat was examined histologically in order to establish the extent of the lesion and nigral glutamate decarboxylase (GAD) was assayed as a marker of GABAergic terminals. Kainic acid produced in the globus pallidus loss of neuronal perikarya and reactive gliosis. Large multipolar neurons of the globus pallidus were characteristically absent on the lesioned-side. Lesions of the pallidum resulted in a non-significant (5.5%) reduction of nigral GAD. Kainate lesions restricted to the head of the caudate resulted in a significant (19%) drop of nigral GAD, while lesions of the caudate body provided the largest reductions of nigral GAD (53%). Lesions of the caudate tail were without effect. The results indicate that nigral GAD arises mostly from the body and, in part, also from the head of the caudate but not from the globus pallidus or from the tail of the caudate.

Animals↗
PubMed2003

Glutamic acid decarboxylase and ICA512/IA-2 autoantibodies as disease markers and relationship to residual beta-cell function and glycemic control in young type 1 diabetic patients.

Circulating autoantibodies (Ab) to islet autoantigens, glutamic acid decarboxylase (GAD(65)), and tyrosine phosphatase ICA512/IA-2 have been proposed as predictive markers of type 1 diabetes mellitus. To ascertain residual beta-cell function and the clinical relevance for monitoring autoimmunity after clinical manifestation of disease, we studied 63 children at diagnosis of type 1 diabetes (mean SD age 7.5 +/- 4 years) and 91 adolescent patients with type 1 diabetes (age 14.7 +/- 1.6 years) with a mean duration of disease of 7 +/- 3.5) years. Forty-two normal adolescent subjects (age 14.6 +/- 1.8 years) without a family history of diabetes were the control group. Anti-GAD(65) and ICA512/IA-2 Ab were assessed by a quantitative radioimmunoprecipitation assay. The relationship between humoral autoimmunity and clinical parameters was explored. GAD(65) and ICA512/IA-2 Ab were detected in 56% and 63% of newly diagnosed children and the prevalence was not different in relationship to clinical characteristics. Levels of GAD(65) Ab positively correlated with diagnosis age (P <.05). Both Ab were associated with islet cell antibodies (ICA) (P <.05), but one fifth of patients had at least 1 of the 2 Ab and absent ICA. At onset, only age showed a significant relationship to residual C-peptide secretion. Among the cohort of patients with diabetes of short-mid duration, GAD(65) and ICA512/IA-2 Ab were present in 44% and 45% of cases (P >.05 and P <.05 v newly diagnosed children, respectively) and more patients were identified by these Ab (68%) than by ICA alone (34%) (P <.05). In this cohort, levels of ICA512/IA-2 Ab negatively correlated with levels of glycosylated hemoglobin (HbA(1c)) (P <.005) and with daily insulin requirement (P <.05). Moreover, the presence of some residual C-peptide secretion was significantly associated with the presence of ICA512/IA-2 Ab (P <.05). Our findings confirm that positivity for either GAD(65) or ICA512/IA-2 Ab is a highly sensitive marker of type 1 diabetes in the pediatric age group, identifying a group of patients with absent ICA immunofluorescence. The persistence of Ab to islet tyrosine phosphatase possibly represents a marker of better glycemic control and less insulin requirement, indicating residual beta-cell function, thus conferring clinical and prognostic relevance to these Ab, as well as potential usefulness in intervention strategies.

Adolescent↗
PubMed1989

Localization of L-glutamic acid decarboxylase mRNA in cat retinal horizontal cells by in situ hybridization.

Retinal horizontal cells receive synaptic input from photoreceptors and provide a pathway for lateral interactions in the vertebrate retina. In nonmammalian retinas, the H1 horizontal cells appear to use gamma-amino butyric acid (GABA) as their neurotransmitter. The transmitter used by mammalian horizontal cells, however, remains to be identified. In the present study, we have employed in situ hybridization to examine whether cat retinal horizontal cells contain L-glutamic acid decarboxylase (GAD) mRNA and hence might use GABA as their transmitter. In the cat retina, labeled cell bodies were found in the inner nuclear layer and the ganglion cell layer. No labeled cells were found in the photoreceptor layer. In the inner nuclear layer, labeled somata were present at two locations. The majority of them (approximately 72%) were located in the vitread side of the inner nuclear layer bordering the inner nuclear layer/inner plexiform layer boundary. A second class of labeled cells in the inner nuclear layer (approximately 20%) had larger somata and were present at the inner nuclear layer/outer plexiform layer boundary. Double labeling experiments with antisera to parvalbumin, a horizontal cell marker, showed that these perikarya belonged to horizontal cells. RNA blot analysis showed that cat retina contains a single species of GAD mRNA that is about 4 kb in size. These data show that in addition to GABAergic amacrine, displaced amacrine, and interplexiform cells described previously, horizontal cells contain GAD mRNA and may use GABA as their neurotransmitter. Hence, GABA may be a transmitter that is involved in lateral inhibition in both nonmammalian and mammalian retinas.

Animals↗
PubMed1977

On the specificity of the uridine diphospho-N-acetylmuramyl-alanyl-D-glutamic acid: diamino acid ligase of Bifidobacterium globosum.

The peptidoglycan of Bifidobacterium globosum contains ornithine and lysine alternately in the same position of the peptide subunit. The uridine diphospho-N-acetylmuramyl-alanyl-D-glutamic acid: diamino acid ligase of this organism was purified 700-fold. Since the activities for the incorporation of ornithine and lysine into uridine diphospho-N-acetylmuramyl-tripeptide did not separate during purification and since the incorporation of ornithine is competitively inhibited by lysine and vice versa, both ornithine and lysine are assumed to be incorporated by one single enzyme. Studies on the specificity of the ligase toward analogs of ornithine have shown that the enzyme requires a diamino, monocarboxylic acid with 4-6 carbon atoms. Methylation of the epsilon-amino group or hydroxylation of the delta-carbon atom of lysine decreases the competitive properties of the analog, whereas the substitution of the gamma-methylen group by sulfur (S-2-aminoethyl cysteine) results in a highly competitive compound.

Actinomycetaceae↗
PubMed2000

Enzymatic breakdown of poly-gamma-D-glutamic acid in Bacillus licheniformis: identification of a polyglutamyl gamma-hydrolase enzyme.

A polyglutamyl gamma-hydrolase enzyme has been identified which catalyses the hydrolytic breakdown of poly-gamma-D-glutamic acid (PGA) from Bacillus licheniformis 9945a. The enzyme was found to be physically associated with the polymer and was activated by Zn2+ or Ca2+ salts. The enzyme can be solubilized from the polymer by treatment with 0.5% SDS and 1 mM ZnCl2 and can then be renatured onto exogenous PGA upon dilution below the detergent critical micellar concentration. The enzyme was partially purified by affinity chromatography, using immobilized PGA. Peptide thioesters containing one and two gamma-glutamyl units were synthesized as potential chromogenic substrates but showed no activity with the solubilized enzyme. Examination of 14C-labeled reaction products indicated that the enzyme is an endo-type hydrolase.

Bacillus↗
PubMed1990

Effects of N-acetyl-aspartyl glutamic acid and sodium cromoglycate on leukotriene B4 secretion by human leukocytes.

Peripheral leukocytes from allergic subjects were treated for 30 min with sodium cromoglycate (SCG) or with N-acetyl-aspartyl glutamic acid (NAAGA) and challenged for leukotriene B4 (LTB4) production with calcium ionophore A 23187. NAAGA significantly inhibits LTB4 release at concentrations of 10(-2) M (-86%), 5 x 10(-3) M (-49%) and 10(-3) M (-34%), while SCG was not able to block LTB4 production within the range of 10(-2)-10(-4) M. In spite of the fact that SCG and NAAGA are chemically unrelated and that both show antiallergic properties, only NAAGA is able in this model to block production of LTB4, a chemical mediator strongly involved in inflammatory and hypersensitivity reactions.

Bronchodilator Agents↗
PubMed1989

[Evaluation of the efficacy of the magnesium salt of N-acetyl-aspartyl-glutamic acid in the treatment of acute rhinitis].

The object of the above study was to evaluate the tolerability and possible therapeutic use of MgNAAGA (Mg salt of N-acetyl-aspartyl-glutamic acid) in patients with allergic rhinitis. Out of 22 subjects with respiratory allergy, 12 were treated for 15 days with MgNAAGA and 10 with DSCG for the same length of time. During this period, patients kept a diary in which they recorded the following symptoms: rhinorrhea, itching, sneezing and nasal obstruction. The trial drug was found to be well tolerated and not to give rise to relevant side effects. The therapeutic efficacy was similar to that of DSCG.

Administration, Intranasal↗
PubMed1980

Isolation and sequence of the vitamin K-dependent protein from human bone. Undercarboxylation of the first glutamic acid residue.

The gamma-carboxyglutamate-containing protein from human bone has been isolated from proteins released upon demineralization of bone by using a combination of gel filtration and immunoadsorption onto a column of immobilized antibody. The sequence of the protein has been determined by automatic sequence analysis of the whole protein and of peptides isolated from tryptic and Staphylococcus aureus protease digests. The protein consists of 49 amino acids in a single polypeptide chain, contains 2 residues of gamma-carboxyglutamic acid, and a single disulfide bond. There are 4 translational substitutions between the human and calf bone proteins and 23 translational substitutions between the human and swordfish bone proteins. Glu-17 was found to be only 9% gamma-carboxylated, while sequence positions 21 and 24 are fully gamma-carboxylated. The identification of glutamic acid at position 17 represents the first instance where a partially gamma-carboxylated glutamate has been found in a sequence position which is to the NH2-terminal side of a gamma-carboxyglutamate residue. The possible significance of this observation is discussed.

1-Carboxyglutamic Acid↗
PubMed2004

Distribution and development of glutamic acid decarboxylase immunoreactivity in the spinal cord of the dogfish Scyliorhinus canicula (elasmobranchs).

The adult distribution and development of gamma-aminobutyric acid (GABA)-synthesizing cells and fibers in the spinal cord of the lesser spotted dogfish (Scyliorhinus canicula L.) was studied by means of immunohistochemistry using antibodies against glutamic acid decarboxylase (GAD). Complementary immunostaining with antibodies against GABA, tyrosine hydroxylase (TH), and HuC/HuD (members of the Hu/Elav family of RNA-associated proteins) and staining with a reduced silver procedure ("en bloc" Bielschowski method), Nissl, and hematoxylin were also used. In adults, GAD-immunoreactive (GAD-ir) cells were observed in the ventral horns, in the spinal nucleus of the dorsal horn, at the base of the dorsal horns, and around the central canal, where some GAD-ir cells were cerebrospinal fluid-contacting (CSF-c). In addition, a few GAD-ir cells were observed in the lateral funiculus between the ventral horn and the marginal nucleus. The adult spinal cord was richly innervated by GAD-ir fibers. Large numbers of GAD-ir fibers and boutons were observed in the dorsal and ventral horns and also interstitially in the dorsal, lateral, and ventral funiculi. In addition, a rich GAD-ir innervation was observed in the marginal nucleus of the spinal cord. In the embryonic spinal cord, GAD-ir cells develop very early: The earliest cells were observed in the very thin mantle/marginal layer of stage 22 embryos in a short length of the spinal cord. At stages 25 and 26, several types of GAD-ir cells (commissural and noncommissural) were distinguished, and two of these cells were of CSF-c type. At stages 28, 30, and 31, the GAD-ir populations exhibited a marked longitudinal columnar organization. Double-immunolabeling experiments in embryos showed the presence of two different GAD-ir CSF-c cell populations, one ventral that is simultaneously TH-ir and other more dorsal that is TH-negative. By stage 33 (prehatching), GAD-expressing cells are present in virtually all loci, as in adults, especially in the ventral horn and base of the dorsal horn. The present results for the lesser spotted dogfish suggest an important role for gamma-aminobutyric acid in sensory and motor circuits of the spinal cord.

Animals↗
PubMed2001

Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65).

T cell recognition of autoantigens is critical to progressive immune-mediated destruction of islet cells, which leads to autoimmune diabetes. We identified a naturally presented autoantigen from the human islet antigen glutamic acid decarboxylase, 65-kDa isoform (GAD65), by using a combination of chromatography and mass spectrometry of peptides bound by the type I diabetes (insulin-dependent diabetes mellitus, IDDM)-associated HLA-DR4 molecule. Peptides encompassing this epitope-stimulated GAD65-specific T cells from diabetic patients and a DR4-positive individual at high risk for developing IDDM. T cell responses were antagonized by altered peptide ligands containing single amino acid modifications. This direct identification and manipulation of GAD65 epitope recognition provides an approach toward dissection of the complex CD4(+) T cell response in IDDM.

Adolescent↗
PubMed1973

Induction of B cell tolerance in vitro to 2,4-dinitrophenyl coupled to a copolymer of D-glutamic acid and D-lysine (DNP-D-GL).

Spleen cells from CBA or congenitally athymic ("nude") mice were pretreated with various concentrations of DNP coupled to a copolymer of D-glutamic acid and D-lysine (DNP(37)-D-GL), under various conditions of time and temperature. After washing, they were then cultured for 3 days with the direct B cell immunogen, DNP coupled to Salmonella adelaide flagella (DNP-FLA). Under all circumstances tried, exposure of cells to 1 microg/ml DNP-D-GL caused a 70-100% depression in the subsequent DNP-specific PFC response, and 100 ng/ml caused a lesser but still substantial effect. At the concentrations used, DNP-D-GL did not affect irrelevant antibody responses. Though cells from nude mice responded somewhat less well to DNP-FLA than those from CBA mice, no significant difference in the reaction of the two populations to the tolerogen was noted. This demonstrates that DNP-D-GL can, as previously suspected, directly cause unresponsiveness in B lymphocytes.

Animals↗
PubMed2001

Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice.

We previously demonstrated that administration of plasmid DNAs (pDNAs) encoding IL-4 and a fragment of glutamic acid decarboxylase 65 (GAD65) fused to IgGFc induces GAD65-specific Th2 cells and prevents insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To assess the general applicability of pDNA vaccination to mediate Ag-specific immune deviation, we examined the immunotherapeutic efficacy of recombinants encoding murine insulin A and B chains fused to IgGFc. Insulin was chosen based on studies demonstrating that administration of insulin or insulin B chain by a variety of strategies prevents IDDM in NOD mice. Surprisingly, young NOD mice receiving i.m. injections of pDNA encoding insulin B chain-IgGFc with or without IL-4 exhibited an accelerated progression of insulitis and developed early diabetes. Exacerbation of IDDM correlated with an increased frequency of IFN-gamma-secreting CD4(+) and CD8(+) T cells in response to insulin B chain-specific peptides compared with untreated mice. In contrast, treatment with pDNAs encoding insulin A chain-IgGFc and IL-4 elicited a low frequency of IL-4-secreting Th cells and had no effect on the progression of IDDM. Vaccination with pDNAs encoding GAD65-IgGFc and IL-4, however, prevented IDDM. These results demonstrate that insulin- and GAD65-specific T cell reactivity induced by pDNA vaccination has distinct effects on the progression of IDDM.

Aging↗
PubMed1985

Glutamic acid decarboxylase-like immunoreactive neurites in senile plaques.

In the neocortex of an aged (26-year-old) rhesus monkey, a small percentage of abnormal neurites within some senile plaques (defined by the presence of amyloid) were immunoreactive for glutamic acid decarboxylase. This suggests that gamma-aminobutyric acid-synthesizing neurons may contribute to plaque formation in the aged brain.

Aging↗
PubMed1992

Determination of D-alanine and D-glutamic acid in biological samples by coupled-column chromatography using beta-cyclodextrin as mobile phase additive.

A high-performance liquid chromatographic assay for monitoring traces of D-alanine and D-glutamic acid in peptide and protein hydrolysates is presented, which uses a two-column set-up with column switching. The main advantage of the proposed method is the higher reliability of the results, compared with the analysis by derivatization and single-column chromatography of the diastereomers. A non-chiral alkyl-silica reversed-phase column is combined with a second column, in which beta-cyclodextrin is used as a chiral mobile phase additive. The amino acids of the hydrolysate are dansylated, and the amino acid of interest is separated from the others on the first column and transferred to the second column where chiral resolution is performed. The transfer volume of ca. 200 microliters is small enough not to cause any peak distortion or dilation in the second column.

Alanine↗