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PubMed1976

Effects of glutamic acid relatives on the electrical activity of an identified molluscan giant neurone (Achatina fulica Férussac).

Effects of glutamic acid and its relatives were examined on the electrical activity of two kinds of neurones (the PON, periodically oscillating neurone, and the TAN, tonically autoactive neurone) identified in the suboesophageal ganglia of an African giant snail, Achatina fulica Férussac. L- and D-Glu, L-Asp, Gly and beta-Ala did not show any effect on the two neurones. However, beta-hydroxyglutamic acid (BHGA) showed a remarkable inhibitory effect on the PON. Erythro-L-BHGA had the strongest effect of these stereoisomers, and the critical concentration of this substance to produce the effect was 10(-6)-3 X 10(-5) g/ml (6-18 muM) when administered in the bath application. We confirmed by the microdrop application that erythro-L-BHGA directly hyperpolarized the PON neuromembrane. When the curve of current-voltage relationships (I-V curve) of the PON neuromembrane measured under erythro-L-BHGA at 10(-5) g/ml (61 muM) was superimposed on the curve of the normal state using the firing level as the common standard, these two curves showed concordance in a wide range of membrane polarization level. This concordance implies that the membrane resistance was maintained normally under erythro-L-BHGA at this concentration. A higher concentration of 10(-4) g/ml (0.61 mM) of this substance caused a decrease of PON membrane resistance and a remarkable elevation of its firing level. The TAN was not sensitive to BHGA, but sensitive to GABA and its derivatives.

Amino Acids↗
PubMed2003

Neonatal monosodium glutamate treatment modifies glutamic acid decarboxylase activity during rat brain postnatal development.

Monosodium glutamate (MSG) produces neurodegeneration in several brain regions when it is administered to neonatal rats. From an early embryonic age to adulthood, GABA neurons appear to have functional glutamatergic receptors, which could convert them in an important target for excitotoxic neurodegeneration. Changes in the activity of the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD), have been shown after different neuronal insults. Therefore, this work evaluates the effect of neonatal MSG treatment on GAD activity and kinetics in the cerebral cortex, striatum, hippocampus and cerebellum of the rat brain during postnatal development. Neonatal MSG treatment decreased GAD activity in the cerebral cortex at 21 and 60 postnatal days (PD), mainly due to a reduction in the enzyme affinity (K(m)). In striatum, the GAD activity and the enzyme maximum velocity (V(max)) were increased at PD 60 after neonatal MSG treatment. Finally, in the hippocampus and cerebellum, the GAD activity and V(max) were increased, but the K(m) was found to be lower in the experimental group. The results could be related to compensatory mechanisms from the surviving GABAergic neurons, and suggest a putative adjustment in the GAD isoform expression throughout the development of the postnatal brain, since this enzyme is regulated by the synaptic activity under physiological and/or pathophysiological conditions.

Animals↗
PubMed1993

Dopaminergic regulation of glutamic acid decarboxylase mRNA expression and GABA release in the striatum: a review.

1. The majority of neurons in the striatum (caudate-putamen, dorsal striatum; nucleus accumbens, ventral striatum) and in striatal projection regions (the pallidum, the entopeduncular nucleus and substantia nigra reticulata) use gamma-aminobutyric acid (GABA) as transmitter and express glutamic acid decarboxylase (GAD; rate limiting enzyme) in the synthesis of GABA. GABA is the major inhibitory transmitter in the mammalian brain. 2. GAD in brain is present as two isoenzymes, GAD65 and GAD67. GAD65 is largely present as an inactive apoenzyme, which can be induced by nerve activity, while most GAD67 is present as a pyridoxal phosphate-bound permanently active holoenzyme. Thus GAD65 and GAD67 seem to provide a dual system for the control of neuronal GABA synthesis. 3. GAD mRNA expression can be visualised and quantified using in situ hybridisation, and GABA release can be quantified using in vivo microdialysis. 4. Different populations of GABA neurons can be distinguished in both dorsal and ventral striatum as well as in other parts of the basal ganglia. 5. Inhibition of dopaminergic transmission in the striatum by lesion of dopamine neurons or by neuroleptic treatment is followed by an increased release of GABA and increased expression of GAD67 mRNA in a subpopulation of striatal medium-sized neurons which project to the globus pallidus, and increased striatal GAD enzyme activity. 6. Increased dopaminergic transmission by repeated but not single doses of amphetamine is followed by decreased striatal GABA release and decreased GAD67 mRNA expression in a subpopulation of medium-sized neurons in the striatum. 7. Two populations of medium-sized GABA neurons in the striatum seem to be under tonic dopaminergic influence. The majority of these GABA neurons are under inhibitory influence, whereas a small number seem to be stimulated by dopamine. 8. Specific changes in activity in subpopulations of striatal GABA neurons probably mediate the dopamine-dependent hypokinetic syndrome seen in Parkinson's disease and following neuroleptic treatment.

Animals↗
PubMed2005

Clinical and genetic characteristics of diabetic patients with high-titer (>10,000 U/ml) of antibodies to glutamic acid decarboxylase.

We investigated the clinical aspects and genetic background of 13 diabetic patients with high-titers (>10,000 U/ml) of anti-glutamic acid decarboxylase antibody (Group A) and compared these 28 middle-aged (35-51 years, Group B) and 13 elderly (66-79 years, Group C) patients with anti-GAD(+) (<1100 U/ml) who were diagnosed initially as having type 2 diabetes. The mean age and mean age at onset of Group A were 70.8 +/- 3.9 years (range, 64-78) and 50.4 +/- 5.4 years (range, 43-61), respectively. In Group A, the prevalence of insulin-deficient patients was significantly lower (30.8%, 4 of 13) than in Group C (96.3%, 27 of 28, P < 0.001). Patients in Group A had a significantly longer interval between the clinical onset of diabetes to initiation insulin therapy (21.8 +/- 2.3 years) compared to patients in both Group B (1.8+/-1.1 years, P < 0.001) and Group C (14.8 +/- 7.1 years, P = 0.049). The frequency of DRB1*0405-DQB1*0401/DRB1*1502-DQB1*0601 or DRB*1501-DQB*0602 heterozygous genotypes in Group A (53.8%, 7 of 13) was significantly higher than in both Group B (3.6%, 1 of 28, P < 0.01) and Group C (7.7%, 1 of 13, P < 0.05). Compared with Group B, Group A had an increased frequency of the TNFA-U01 haplotype and the IL-10 -592 C allele (TNFA-U01; 53.8% versus 30.4%, P = 0.05 and IL-10 -592 C; 57.7% versus 33.9 %, P = 0.042). All sera from Group A reacted with GAD(65) protein on Western blots. We conclude that adult-onset diabetic patients with a high-titer of anti-GDAab differ from patients with latent autoimmune diabetes mellitus in adult (LADA) with respect to beta-cell function, cellular autoimmunity and genetic background. Our study also showed that high-titers of antibodies to glutamic acid decarboxylase (anti-GADab) were not predictive of later development of insulin deficiency in adult and/or elderly patients with type 2 diabetes. Furthermore, our results suggest that HLA-DRB1*1502-DQB1*0601 or DRB1*1501-DQB1*0602/DRB1*0405-DQB1*0401 heterozygous genotypes may be associated with high production of anti-GADab that recognizes the linear epitope(s) on the GAD(65) protein.

Adult↗
PubMed1993

Glutamic acid and gamma-aminobutyric acid modulate each other's release through heterocarriers sited on the axon terminals of rat brain.

The effects of gamma-aminobutyric acid (GABA) on the spontaneous release of endogenous glutamic acid (Glu) or aspartic acid (Asp) and the effects of Glu on the release of endogenous GABA or [3H]GABA were studied in superfused rat cerebral cortex synaptosomes. GABA increased the outflow of Glu (EC50 17.2 microM) and Asp (EC50 18.4 microM). GABA was not antagonized by bicuculline or picrotoxin. Neither muscimol nor (-)-baclofen mimicked GABA. The effects of GABA were prevented by GABA uptake inhibitors and were Na+ dependent. Glu enhanced the release of [3H]GABA (EC50 11.5 microM) from cortical synaptosomes. Glu was not mimicked by the glutamate receptor agonists N-methyl-D-aspartic, kainic, or quisqualic acid. The Glu effect was decreased by the Glu uptake inhibitor D-threo-hydroxyaspartic acid (THA) and it was Na+ sensitive. Similarly to Glu, D-Asp increased [3H]GABA release (EC50 9.9 microM), an effect blocked by THA. Glu also increased the release of endogenous GABA from cortex synaptosomes. In this case the effect was in part blocked by the (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, whereas the 6-cyano-7-nitroquinoxaline-2,3-dione-insensitive portion of the effect was prevented by THA. GABA increased the [3H]D-Asp outflow (EC50 13.7 microM) from hippocampal synaptosomes in a muscimol-, (-)-baclofen-, bicuculline-, and picrotoxin-insensitive manner. The GABA effect was abolished by blocking GABA uptake and was Na+ dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Transport System X-AG↗
PubMed1972

Glutamic acid mimicking of synaptic inhibition on the giant serotonin neurone of the snail.

Stimulation of the snail's tentacle nerves results in hyperpolarization and inhibition of the 'giant serotonin-containing neurone'located in the brain. Glutamic acid mimics this effect. Available data indicate that the reversal potential for the glutamic acid effect is very similar to that of the synaptic action being about 5 to 8 mV more negative than the resting potential in each case.

Action Potentials↗
PubMed1998

[Effects of glutamic acid and acetylcholine on induction of heat shock proteins 70 mRNA in PC12 cells].

The heat shock response has been found in many strains of bacteria to human beings. Besides heat stimuli, many kinds of factors could also induce the synthesis of heat shock proteins (hsp). It is still unknown whether neurotransmitter could induce the increase of hsp expression in mammalian cells. In the present study, the effects of glutamic acid and acetylcholine (ACh) on the induction of hsp70 mRNA in PC12 cells were studied by Northern blot method. The probe used is specific for inducible hsp70 mRNA. Our results showed that the glutamic acid under limited conditions (such as at 50-500 mumol/L and action time 5-30 min) could induce the expression of hsp70 mRNA, which was partly mediated by NMDA receptors. On the other hand, ACh (0.1-1,000 mumol/L) could not induce the expression of hsp 70 mRNA.

Acetylcholine↗
PubMed1993

[Effects of electroacupuncture at different frequencies on the nociceptive response and central contents of GABA and glutamic acid in arthritic rats].

It has been demonstrated that electroacupuncture (EA) produces analgesia in acute arthritic animal models, while the differential analgesic effects at different EA parameters remains to be discovered. In the present experiment, the effects of EA at 100 Hz and 15 Hz on bilateral Yanglingpuan acupoints of the arthritic rats was studied. The results showed: 1) 15Hz EA was more effective than 10Hz EA for analgesia; 2) spinal glutamic acid content of the 15-Hz EA group was significantly lower than that of the 100-Hz EA group, and 3) no significant difference in GABA contents between the two groups was found. The results suggest that spinal glutamic acid may be involved in the different analgesic effects of EA at different frequencies in arthritic rats.

Acupuncture Analgesia↗
PubMed1999

Multiplicity of glutamic acid decarboxylases (GAD) in vertebrates: molecular phylogeny and evidence for a new GAD paralog.

The evolution of chordate glutamic acid decarboxylase (GAD; EC 4.1.1.15), a key enzyme in the central nervous system synthesizing the neurotransmitter gamma-amino-butyric acid (GABA) from glutamate, was studied. Prior to this study, molecular data of GAD had been restricted to mammals, which express two distinct forms, GAD65 and GAD67. These are the products of separate genes and probably are derived from a common ancestral GAD following gene duplication at some point during vertebrate evolution. To enable a comprehensive phylogenetic analysis, molecular information of GAD forms in other vertebrate classes was essential. By reverse transcriptase-polymerase chain reaction (RT-PCR), partial nucleotide sequences of GAD were cloned from brains of zebra finch (Taeniopygia guttata), turtle (Trachemys scripta), goldfish (Carassius auratus), zebrafish (Danio rerio), and armoured grenadier (Coryphaenoides (Nematonurus) armatus, a deep-sea fish), and from the cerebral ganglion plus neural gland of Ciona intestinalis, a protochordate. Whereas GAD65 and GAD67 homologs were expressed in birds, reptiles, and fish, only a single GAD cDNA with equal similarities to both vertebrate GAD forms was found in the protochordate. This indicates that the duplication of the vertebrate GAD gene occurred between 400 and 560 million years ago. For both GAD65 and GAD67, the generated phylogenetic tree followed the general tree topology for the major vertebrate classes. In turtle, an alternative spliced form of GAD65, putatively encoding a truncated, nonactive GAD, was found. Furthermore, a third GAD form, which is equally divergent from both GAD65 and GAD67, is expressed in C. (N.) armatus. This third form might have originated from an ancient genome duplication specific to modern ray-finned fishes.

Alternative Splicing↗
PubMed1999

Glutamic acid decarboxylase mRNA in the suprachiasmatic nucleus of rats housed in constant darkness.

This study demonstrates that the levels of the mRNAs encoding the two isoforms of glutamic acid decarboxylase (GAD) (i.e., GAD65 and GAD67) do not differ over the circadian activity cycle in the suprachiasmatic nucleus (SCN) of rats housed in constant darkness. These data indicate that the rhythmic expression of GAD56 mRNA previously observed in animals housed in a light:dark cycle [K.L. Huhman, A.C. Hennessey, H.E. Albers, Rhythms of glutamic acid decarboxylase mRNA in the suprachiasmatic nucleus, J. Biol. Rhythms 11 (1996) 311-316.] is the result of the activity of retinal afferents.

Animals↗
PubMedDate not supplied

Insulinotropic response to enterally administered succinic and glutamic acid methyl esters.

Both the monomethyl and dimethyl esters of succinic acid, administered enterally to fasted rats, caused a rapid increase in plasma insulin. Such was not the case, however, after enteral administration of either succinic acid or the dimethyl ester of glutamic acid. The time course for the appearance of radioactive material in plasma was also vastly different after enteral administration of either [1,4-14C]succinic acid or its dimethyl ester. In the latter case, the separation of acidic and nonacidic radioactive metabolites and the measurement of 14C-labelled D-glucose indicated that, after enteral administration of succinic acid dimethyl ester (2 mmol), its initial appearance rate in plasma averaged 45 +/- 9 microM/min resulting, after 120 min, in a plasma concentration of 1.34 +/- 0.14 mM.

Animals↗
PubMed1997

Glutamic acid 286 in subunit I of cytochrome bo3 is involved in proton translocation.

Glutamic acid 286 (E286; Escherichia coli cytochrome bo3 numbering) in subunit I of the respiratory heme-copper oxidases is highly conserved and has been suggested to be involved in proton translocation. We report a technique of enzyme reconstitution that yields essentially unidirectionally oriented cytochrome bo3 vesicles in which proton translocation can be measured. Such experiments are not feasible in the E286Q mutant due to strong inhibition of respiration, but this is not the case for the mutants E286D and E286C. The reconstituted E286D mutant enzyme readily translocates protons whereas E286C does not. Loss of proton translocation in the D135N mutant, but not in D135E or D407N, also is verified using proteoliposomes. Stopped-flow experiments show that the peroxy intermediate accumulates in the reaction of the E286Q and E286C mutant enzymes with O2. We conclude that an acidic function of the 286 locus is essential for the mechanism of proton translocation.

Cytochrome b Group↗
PubMed2002

Role of glutamic acid decarboxylase in the pathogenesis of type 1 diabetes.

Glutamic acid decarboxylase (GAD) is considered to be one of the strongest candidate autoantigens involved in triggering beta-cell-specific autoimmunity. The majority of recent onset type 1 diabetes patients and pre-diabetic subjects have anti-GAD antibodies in their sera, as do nonobese diabetic (NOD) mice, one of the best animal models for human type I diabetes. Immunization of young NOD mice with GAD results in the prevention or delay of the disease as a result of tolerizing autoreactive T cells. Autoimmune diabetes can also be prevented by the suppression of GAD expression in antisense GAD transgenic mice backcrossed with NOD mice for seven generations. These results support the hypothesis that GAD plays an important role in the development of T-cell-mediated autoimmune diabetes. However, there is some controversy regarding the role of GAD in the pathogenesis of diabetes. Whether GAD truly plays a key role in the initiation of this disease remains to be determined. The examination of the development of insulitis and diabetes in beta-cell-specific GAD knockout NOD mice will answer this remaining question.

Amino Acid Sequence↗
PubMed2004

Preparation and thermosensitivity of naturally occurring polypeptide poly(gamma-glutamic acid) derivatives modified by propyl groups.

Poly(gamma-glutamic acid) (gamma-PGA) is a biosynthetic polymer, and the carboxyl groups are able to undergo a chemical modification. In this study, poly(alpha-propyl gamma-glutamate) (gamma-PGA propylate) was synthesized by the esterification of these carboxyl groups to yield a thermosensitive and biodegradable polymer. In aqueous solution, the gamma-PGA propylate can impart thermosensitivity by controlling the hydrophobic-hydrophilic balance of the gamma-PGA polymeric chains.

Drug Stability↗
PubMed1994

Monoclonal antibodies specific to the glutamic acid decarboxylase 65 kDa isoform derived from a non-obese diabetic (NOD) mouse.

Two monoclonal antibodies specifically recognizing the 65 kDa isoform of the enzyme glutamic acid decarboxylase (GAD) were generated by fusion of spleen cells of a non-obese diabetic (NOD) mouse which had received a single intraperitoneal injection of 0.2 ml complete Freund's adjuvant followed three days later by one administration of a subdiabetogenic dose of streptozotocin (80 mg/kg body weight) three days before the fusion experiment was performed. Both monoclonals belong to the IgG1 isotype and were screened with an enzyme-linked immunosorbent assay using rat brain extract as a natural source of GAD and additionally with a capture assay by means of immunoglobulins of a patient with Stiff-man syndrome. The specific binding to the 65 kDa isoform of the enzyme was detected by a radioligand and an enzyme-linked immunosorbent assay using recombinant human glutamic acid decarboxylase specific for both the 67 and 65 kDa isoforms. Both monoclonal antibodies recognize the same antigenic epitope, which is located in the N-terminal region of the first 17 amino acids detected by fragments of human pancreatic 65 kDa GAD. Three out of 30 sera from Type 1 diabetic patients specifically displaced the binding of the monoclonals from 125I-labelled GAD65 measured by radio-immunoassay. A striking binding of both monoclonals M61/8F9 and M61/7E11 to the islets of cryosections of human, monkey, pig and rat pancreas but not to mouse pancreas was detectable. The antibodies failed to bind on the cell surface of viable rat islet cells. It is concluded that also in the diabetes-prone NOD mice GAD65 autoantibodies occur although GAD65 was not detectable in the mouse islets.

Animals↗
PubMedDate not supplied

Antibodies to glutamic acid decarboxylase in Syrian and Jordanian type I diabetes patients and their siblings.

BACKGROUND: Attempts to identify the earliest events in the autoimmune process in type I diabetes mellitus suggests the glutamic acid decarboxylase (GAD) is one of the first and most important autoantigens. We conducted this study to determine the prevalence of antibodies to glutamic acid decarboxylase (anti-GAD) in both Syrian and Jordanian children with Type I diabetes and their siblings. PATIENTS AND METHODS: sera were obtained from 85 Syrian patients with type I diabetes (mean age 13.6 + 5.9 years), from 45 of their siblings (mean age 11 + 6.1 years), from 78 randomly selected Syrian control subjects (mean age 9.9 + 43 years), and from 95 Jordanian patients with type I diabetes (mean age 13.9 + 65 years), from 78 of their siblings (mean age 12.3 + 7.1 years), and from 100 randomly selected Jordanian control subjects (mean age 7.8 + 4.5 years). Sera were analyzed from anti-GAD using the enzyme linked immunosorbent assay (ELISA) technique. RESULTS: Prevalence of anti-GAD was 34.1% (29/85) in Syrian type I diabetes patients, 20% (9/45) in their siblings, 1.3% (1/78) in Syrian control subjects, 49.5% (47/95) in Jordanian type I diabetes patients, 23% (18/78) in their siblings, and 2% (2/100) in Jordanian control subjects. Differences between the Syrian and Jordanian type I diabetes groups and their siblings and controls were statistically significant. In patients with less than two years of diabetes duration, the frequency was 88.8% (16/18) for both groups. There was no correlation between sex and anti-GAD levels in their Syrian and Jordanian type I diabetes patients and their siblings. The positivity of anti-GAD tended to be more frequent at the age range of 5 to 8 years in siblings. Anti-GAD titers >90 ng/ml were found in 58.8% of type I diabetes patients and in 38% of siblings who were anti-GAD positive. CONCLUSION: Syria and Jordan have prevalence rates of anti-GAD among type I diabetes patients and their siblings that are among the highest reported in the world. Therefore, anti-GAD may be valuable as an early predictive marker for type I diabetes.

Journal Article↗
PubMedDate not supplied

[Age-related changes in the blood-brain barrier in the rat with reference to methionine, lysine, glutamic acid and N-methyl-N-nitrosourea].

One possible cause of the decline in brain function with aging might be an age-related change in the blood-brain barrier (BBB). Therefore, we assessed the "Brain Uptake Index" (BUI) by the method of Oldendorf (1970) in 99 male Sprague-Dawley rats aged 3-4 months (young), 7-11 months (adult) and 28-31 months (old) for the following compounds: methionine, lysine, glutamic acid and N-methyl-N-nitrosourea (MNU). The BUIs of methionine and MNU showed marked but contrasting biphasic changes with age: the adult animals had the highest BUIs for methionine and the lowest for MNU, compared with the young and old groups. With lysine, a declining tendency with age was indicated, whereas no differences could be detected with glutamic acid. The results suggest that the BBB undergoes different changes in development and aging, leading to an optimal amino acid transport and minimum penetration of lipophilic agents (MNU) in the adult brain. Thereafter, the opposite takes place, reducing necessary transport and increasing the penetration of lipophilic compounds.

Aging↗