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PubMed1974

Biological actions in vivo and in vitro of two gamma-aminobutyric acid (GABA) analogues: beta-chloro GABA and beta-phenyl GABA.

1 The synthesis of two analogues of gamma-aminobutyric acid (GABA), beta-chloro GABA and beta-phenyl GABA is described.2 The activity of brain GABA aminotransferase was inhibited by beta-chloro GABA (5.7 x 10(-5)M) and beta-phenyl GABA (4.6 x 10(-3)M) in a competitive manner with GABA.3 beta-Chloro GABA exhibited 50% of the inhibitory activity of GABA in blocking the discharge of the crayfish stretch receptor neurone; beta-phenyl GABA had no detectable effect.4 Injection of beta-phenyl GABA (200 mg/kg) into normal or epileptic cats (cobalt) caused the appearance of synchronized slow-wave EEG activity.5 Administration of beta-chloro GABA (200 mg/kg) to epileptic cats (cobalt) produced a temporary diminution or abolition of epileptic discharges while causing no alteration in normal EEG activity.6 beta-Chloro GABA and beta-phenyl GABA had no effect on the concentrations of catecholamines or of amino acids in mouse brain.7 The results suggest that both beta-chloro GABA and beta-phenyl GABA may pass the blood-brain barrier.

Amino Acids↗
PubMed1985

Inhibitory effect of cephalosporins on gamma-aminobutyric acid receptor binding in rat synaptic membranes.

Cephalosporins inhibited gamma-aminobutyric acid receptor binding in a concentration-dependent manner in vitro. Scatchard analysis revealed that cefazolin decreased the binding capacity but did not change the affinity of the receptor. It is suggested that this inhibition of gamma-aminobutyric acid receptor binding may be involved in the induction of convulsions by cephalosporins.

Animals↗
PubMed1973

The uptake of 3Hp -aminobutyric acid by the retina.

1. The accumulation of (3)H-gamma-aminobutyric acid (GABA) by the isolated rat retina has been measured.2. When retinae were incubated at 37 degrees C in a medium containing (3)H-GABA, tissue:medium ratios of about 25:1 were attained after a 30 min incubation.3. After incubations of 40 min at 37 degrees C, almost all (98%) the radioactivity in the tissue was present as unchanged (3)H-GABA.4. The process responsible for (3)H-GABA uptake showed many of the properties of an active uptake system: it was temperature-sensitive, required the presence of sodium ions in the external medium, was inhibited by anoxia, dinitrophenol and ouabain, and showed saturation kinetics.5. The estimated Km value of GABA was 4.0 x 10(-5)M, and V(max) was 0.167 (mumoles/min)/g retina.6. The uptake of (3)H-GABA was not affected by the presence of large molar excesses of glycine, L-glutamate, L-aspartate, L-alanine, L-proline, or L-histidine, but was inhibited by DL-gamma-amino-beta-hydroxybutyrate, beta-guanidinopropionate, and L-2,4-diaminobutyrate.7. The retina was capable of achieving a large net uptake of GABA, indicating that the accumulation of (3)H-GABA by the tissue was not due only to an exchange process with the endogenous GABA pool.8. The uptake of (3)H-GABA occurred only in tissue from the central nervous system. Thus, retina and cerebral cortex rapidly accumulated radioactivity, but slices of cornea, posterior wall of the eye, and liver achieved tissue: medium ratios of approximately one.9. There was a rapid efflux of radioactivity from retinae placed in fresh medium and after 60 min, 90% of the radioactivity was lost from the tissue. The radioactivity released into the medium was present largely as (3)H-acidic and neutral metabolites. When the metabolism of GABA was inhibited by the presence of amino-oxyacetic acid in the medium, only about 10% of the radio-activity was lost from the tissue during a similar 60 min incubation, and the radioactivity released was present largely as unchanged (3)H-GABA.10. It is suggested that the GABA uptake process may represent a possible mechanism for the inactivation of GABA if this amino acid is released at inhibitory synapses in the retina.

Acetates↗
PubMed1991

2-amino-4-phosphonobutyric acid exerts a light-dependent effect on post-gabaculine levels of retinal gamma-aminobutyric acid (GABA): evidence that ON synaptic pathways regulate retinal GABAergic transmission.

The effects of light, 2-amino-4-phosphonobutyric acid (APB), and kainic acid on rat retinal gamma-aminobutyric acid (GABA)-ergic transmission were studied by measuring levels of retinal GABA following subcutaneous injection of gabaculine, an irreversible inhibitor of GABA-transaminase. Post-gabaculine levels of retinal GABA in light-exposed rats were significantly greater than those in rats held in darkness. The synaptic mechanism of this effect of light was examined by measuring post-gabaculine levels of retinal GABA in rats placed into either lighted or darkened conditions after receiving unilateral intravitreal injections of APB, a glutamate analogue that selectively decreases the activity of ON synaptic pathways in the retina. APB attenuated the post-gabaculine accumulation of GABA in rats held in the light, but not in those placed into darkness. Furthermore, the light-dependent increment in post-gabaculine accumulation of retinal GABA was entirely APB sensitive, and the effect of APB was entirely light dependent. In contrast to APB, kainic acid stimulated the post-gabaculine accumulation of retinal GABA in vivo. Our findings suggest that APB and kainic acid influence GABAergic transmission at different sites in the retina and that some retinal GABAergic neurons are either ON or ON-OFF amacrine cells.

Aminobutyrates↗
PubMed1984

gamma-Aminobutyric acid uptake inhibition and anticonvulsant activity of nipecotic acid esters.

n-Alkyl esters of nipecotic acid were prepared by Fischer esterification, and the esters were evaluated against bicuculline-induced seizures in mice. Evaluation of the alkyl esters for inhibition of gamma-aminobutyric acid uptake into mouse whole brain mini-slices revealed that the order of potency was proportional to chain length. The octyl ester inhibited gamma-aminobutyric acid and beta-alanine uptakes by apparently nonspecific mechanisms. A variety of phenyl esters of nipecotic acid were also synthesized utilizing either dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole as the condensing agent. Most of the phenyl esters were potent inhibitors of gamma-aminobutyric acid uptake. The uptake inhibition appeared to involve specific and nonspecific (detergent-like) mechanisms. The m-nitrophenyl and p-nitrophenyl esters were particularly potent against bicuculline-induced seizures in mice.

Alanine↗
PubMed2000

An intermediate state of the gamma-aminobutyric acid transporter GAT1 revealed by simultaneous voltage clamp and fluorescence.

The rat gamma-aminobutyric acid transporter GAT1 expressed in Xenopus oocytes was labeled at Cys74, and at one or more other sites, by tetramethylrhodamine-5-maleimide, without significantly altering GAT1 function. Voltage-jump relaxation analysis showed that fluorescence increased slightly and monotonically with hyperpolarization; the fluorescence at -140 mV was approximately 0. 8% greater than at +60 mV. The time course of the fluorescence relaxations was mostly described by a single exponential with voltage-dependent but history-independent time constants ranging from approximately 20 ms at +60 mV to approximately 150 ms at -140 mV. The fluorescence did not saturate at the most negative potentials tested, and the midpoint of the fluorescence-voltage relation was at least 50 mV more negative than the midpoint of the charge-voltage relation previously identified with Na(+) binding to GAT1. The presence of gamma-aminobutyric acid did not noticeably affect the fluorescence waveforms. The fluorescence signal depended on Na(+) concentration with a Hill coefficient approaching 2. Increasing Cl(-) concentration modestly increased and accelerated the fluorescence relaxations for hyperpolarizing jumps. The fluorescence change was blocked by the GAT1 inhibitor, NO-711. For the W68L mutant of GAT1, the fluorescence relaxations occurred only during jumps to high positive potentials, in agreement with previous suggestions that this mutant is trapped in one conformational state except at these potentials. These observations suggest that the fluorescence signals monitor a novel state of GAT1, intermediate between the E*(out) and E(out) states of Hilgemann, D.W., and C.-C. Lu (1999. J. Gen. Physiol. 114:459-476). Therefore, the study provides verification that conformational changes occur during GAT1 function.

Animals↗
PubMed1991

gamma-Aminobutyric acid (GABA) stimulates somatostatin release following activation of a GABA uptake carrier located on somatostatin nerve endings of rat cerebral cortex.

The effect of gamma-aminobutyric acid (GABA) on the release of somatostatin-like immunoreactivity (SRIF-LI) was studied in synaptosomes prepared from rat cerebral cortex and exposed in superfusion to the amino acid. GABA (1-300 microM) increased the spontaneous outflow of SRIF-LI in a concentration-dependent manner. The effect of GABA was not prevented by the GABAA receptor antagonists bicuculline or picrotoxin. The GABAA receptor agonist muscimol (10-100 microM) did not affect SRIF-LI release. Similarly ineffective was the GABAB receptor agonist (-)-baclofen (100 microM). The GABA-induced SRIF-LI release was counteracted by the GABA uptake inhibitors N-(4,4-diphenyl-3-butenyl)-nipecotic acid (SK&F 89976A) and nipecotic acid. When used as a GABA carrier substrate, nipecotic acid mimicked GABA and increased SRIF-LI release; its effect was antagonized by SK&F 89976A. The mechanism involved appears to be selective for GABA inasmuch as neutral amino acids such as leucine, alpha-aminobutyric acid or valine, tested at 100 microM, had little or no effect on the release of SRIF-LI. Neither GABA (100 microM) nor nipecotic acid (300 microM) enhanced the release of cholecystokinin-like immunoreactivity. The GABA-evoked somatostatin release was calcium-dependent and tetrodotoxin-insensitive. It is concluded that a carrier for the uptake of GABA exists on somatostatin-releasing terminals of rat cerebral cortex and that GABA uptake may regulate somatostatin release. This conclusion would be compatible with the reported coexistence of GABA and somatostatin in cerebrocortical neurons.

Amino Acids↗
PubMed1985

Mutations affecting the enzymes involved in the utilization of 4-aminobutyric acid as nitrogen source by the yeast Saccharomyces cerevisiae.

We present genetic evidence for the enzymes 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19) and succinate-semialdehyde dehydrogenase [NAD(P)+] (EC 1.2.1.16) constituting the functional pathway for the utilization of 4-aminobutyric acid as a nitrogen source by Saccharomyces cerevisiae. We show that the pathway is induced by 4-aminobutyric acid and that the presence of the pathway enzymes probably requires the integrity of a positive control element.

4-Aminobutyrate Transaminase↗
PubMed1983

Immunocytochemical localization of glutamic acid decarboxylase in normal and deafferented superior colliculus: evidence for reorganization of gamma-aminobutyric acid synapses.

There is circumstantial evidence that GABAergic synaptic terminals in the superior colliculus might become reorganized in response to a loss of the retinal innervation of this brain region. The present investigation tests this possibility by identifying gamma-aminobutyric acid (GABA) neurons and their synaptic relationships with an immunocytochemical localization of the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD), and by comparing these synaptic relationships in normal superior colliculus with those present 6 and 16 weeks after unilateral eye removal. In normal superior colliculus, light microscopy revealed a much denser concentration of GAD-positive reaction product in the superficial layers than in the intermediate and deep collicular layers. Most of this reaction product was contained within small, punctate structures, but GAD-positive somata and proximal dendrites also were observed. Electron microscopy showed that GAD was localized in numerous synaptic terminals, including those that were the presynaptic elements of dendrodendritic synapses. The vast majority of GAD-positive presynaptic elements formed symmetric synaptic junctions. In addition, GAD-positive profiles frequently were postsynaptic to unstained retinal terminals as well as presynaptic to unstained dendritic profiles and thus participated in serial synaptic relationships. Furthermore, both retinal and GAD-positive elements commonly were presynaptic to the same postsynaptic dendrite, and often these synaptic contracts were adjacent to each other. In deafferented specimens, profiles with the characteristics of retinal axon terminals were not observed, whereas there appeared to be no reduction of GAD-positive synaptic profiles. However, there was a marked and statistically significant increase in the proportion of GAD-positive presynaptic terminals that formed asymmetric synaptic contacts in superior colliculus deprived of retinal input. This change indicates that partial deafferentation induces a reorganization of GAD-positive synapses. The long-term presence of the GABA-synthesizing enzyme within reorganized synaptic terminals also suggests that such presynaptic elements could produce and, presumably, release neurotransmitter.

Animals↗
PubMed1978

Automated assay of gamma-aminobutyric acid in human cerebrospinal fluid.

We describe an automated amino acid analyzer with fluorescence detection (o-phthalaldehyde) which permits sensitive and rapid determinations of gamma aminobutyric acid in human cerebrospinal fluid. Concentrations as low as 50 nmol/liter can be accurately determined in 100 mul samples at the rate of one sample per hour. Concentrations in untreated cerebrospinal fluid increase rapidly after sampling by lumbar puncture. The concentration in immediately deproteinized samples from 38 patients with intervertebral disc disorders was 220 +/- 81 nmol/liter (mean +/- SD).

Amino Acids↗
PubMed1989

Studies on gamma-aminobutyric acid production by immobilized Escherichia coli cells.

E. coli cells with glutamate decarboxylase activity were immobilized by entrapment in calcium alginate gel lattices, followed by cross-linking with glutaric dialdehyde to increase mechanical strength. A large number of cells was immobilized in the gel, resulting in high enzyme activity. Optimum conditions for gamma-aminobutyric acid production were investigated. A comparative study of three reactor modes, i.e., batch, continuously stirred, and continuous column, found the optimal pH and temperature for -aminobutyric acid production to be 4.4 and 37 degrees C respectively. The batch process was run on a shaker at 120 r/min, the continuously stirred reaction (in a flask reactor) at 6 ml/h, and column production (in a special column reactor) at 12 ml/h. Conversion of the L-glutamate to gamma-aminobutyric acid was about 85-100% under these conditions. The immobilized cells could be regenerated by incubation in phosphopyridoxal coenzyme solution when enzyme activity and immobilized-cell throughput declined. The column-type process had some advantages over the others.

Alginates↗
PubMed2005

Inhibition of thermal hyperalgesia and tactile allodynia by intrathecal administration of gamma-aminobutyric acid transporter-1 inhibitor NO-711 in rats with chronic constriction injury.

The present study was undertaken to explore the role of gamma-aminobutyric acid transporters in the neuropathic pain. On the chronic constriction injury (CCI) rats 4 doses (5, 10, 20, 40 microg in group N5, N10, N20, N40, respectively) of specific gamma-aminobutyric acid transporter-1 inhibitor NO-711 or normal saline (in group NS) were intrathecally administered before sciatic nerve ligation (pre-treatment) or at the third day after ligation (post-treatment). The paw withdrawl latency (PWL) from a noxious thermal stimulus and paw withdrawl mechanical threshold (PWMT) of von Frey filament was used as measure of thermal hyperalgesia and tactile allodynia respectively. The results demonstrated that post-treatment of NO-711 significantly suppressed thermal hyperalgesia and allodynia in CCI rats (P<0.05, P<0.01), the inhibitory effect lasted for 2 h (N40 group) and 4 h (N20 group) respectively. NO-711 inhibited thermal hyperalgesia induced by CCI in a dose-dependent manner. Intrathecal pretreatment with different doses of NO-711 delayed the occurrence of thermal hyperalgesia, but could not delay the emergence of allodynia induced by CCI. This study indicates that gamma-aminobutyric acid transporter inhibitor has anti-thermal hyperalgesia and anti-tactile allodynia effects in neuropathic rats.

Animals↗
PubMed1998

Temporal oscillations of phosphatases in N-phthaloyl gamma-aminobutyric acid treated rats.

N-pathaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar and 24 hr rhythms of acid and alkaline phosphatases were studied under light-dark conditions. P-GABA administration advanced the peak times of phosphatases. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA might reduce the photic information received by the clock. The results could be explained by slight daily advances which would bring the peak times to the points 21 days after the start of administration.

Acid Phosphatase↗
PubMed1997

gamma-Aminobutyric acid stimulates ethylene biosynthesis in sunflower.

gamma-Aminobutyric acid (GABA), a nonprotein amino acid, is often accumulated in plants following environmental stimuli that can also cause ethylene production. We have investigated the relationship between GABA and ethylene production in excised sunflower (Helianthus annuus L.) tissues. Exogenous GABA causes up to a 14-fold increase in the ethylene production rate after about 12 h. Cotyledons fed with [14C]GABA did not release substantial amounts of radioactive ethylene despite its chemical similarity to 1-aminocyclopropane-1-carboxylic acid (ACC), indicating that GABA is not likely to be an alternative precursor for ethylene. GABA causes increases in ACC synthase mRNA accumulation, ACC levels, ACC oxidase mRNA levels, and in vitro ACC oxidase activity. In the presence of aminoethoxyvinylglycine or alpha-aminoisobutyric acid, GABA did not stimulate ethylene production. We therefore conclude that GABA stimulates ethylene biosynthesis mainly by promoting ACC synthase transcript abundance. Possible roles of GABA as a signal transducer are suggested.

Amino Acid Oxidoreductases↗
PubMed1980

Cellular synthesis and axonal transport of gamma-aminobutyric acid in a photoreceptor cell of the barnacle.

1. [3H]glutamate or [3H]gamma-aminobutyric acid (GABA) was injected into the photoreceptor cell of the lateral ocellus of Balanus eburneus, in order to study the transmitter substance of the cell. 2. The photoreceptor cell synthesized [3H]GABA from injected [3H]glutamate. 3. The newly formed [3H]GABA moved inside the photoreceptor axon towards the axon terminal with a velocity of about 0.9 mm/hr. Injected [3H]GABA moved at 0.9 mm/hr and also at 0.4 mm/hr. 4. Axonally transported [3H]GABA reached the axon terminal within several hours following the injection. It did not accumulate at the terminal, but gradually disappeared. 5. Light-microscope and electron-microscope autoradiography following the injection of [3H]GABA revealed that [3H]-reacted silver grains were present in a certain type of axon terminal. The terminal thus identified as that of a photoreceptor cell contains many clear, polymorphic synaptic vesicles about 300-500 A in diameter, some dense-cored vesicles 700-1300 A in diameter, and glycogen granules. The terminal forms many synapses, and each synapse has a synaptic dense body. The terminal always faces two post-synaptic elements at the synapse, forming a triad with a gap distance of about 160-200 A. 6. A GABA analogue, [3H]di-aminobutyric acid, was selectively taken up into the terminals previously identified as those of photoreceptors. 7. These results support the notion that the transmitter substance of the photoreceptor cell of the barnacle is GABA.

Animals↗
PubMed2001

Overexpression of gamma-aminobutyric acid transporter subtype I leads to susceptibility to kainic acid-induced seizure in transgenic mice.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter, and the GABAergic synaptic transmission is normally terminated by the rapid uptake through GABA transporters. With transgenic mice ubiquitously overexpressing GABA transporter subtype I (GAT1), the present study explored the pathophysiological role of GAT1 in epileptogenesis. Though displaying no spontaneous seizure activity, these mice exhibit altered electroencephalographic patterns and increased susceptibility to seizure induced by kainic acid. In addition, the GABA(A) receptor and glutamate transporters are up-regulated in transgenic mice, which perhaps reflects a compensatory or corrective change to the elevated level of GAT1. These preliminary findings support the hypothesis that excitatory and inhibitory neurotransmission, and seizure susceptibility can be altered by neurotransmitter transporters.

ATP-Binding Cassette Transporters↗
PubMed2001

Identification of SNPs in human gamma aminobutyric acid A receptor gamma2 gene.

Gamma aminobutyric acid (GABA) is a major inhibitory neurotransmitter. Because of its importance and diverse functions, studies of single nucleotide polymorphisms in the GABA receptor genes are of great significance, which may produce useful molecular markers for genetic analysis of neurological disease, and possibly lead to the discovery of pathogenic mutations. We identified eleven SNPs in the entire exon regions, immediate intron regions and promoter region of human GABA receptor gamma2 gene by direct sequencing. In this discovery, 2 non-synonymous cSNPs and 1 splicing variant are found.

Evolution, Molecular↗