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At least 73 records · Page 4Linked to original sources
PubMed1999

Gamma-aminobutyric acid increases the water accessibility of M3 membrane-spanning segment residues in gamma-aminobutyric acid type A receptors.

Gamma-aminobutyric acid type A (GABA(A)) receptors are members of the ligand-gated ion channel gene superfamily. Using the substituted cysteine accessibility method, we investigated whether residues in the alpha(1)M3 membrane-spanning segment are water-accessible. Cysteine was substituted, one at a time, for each M3 residue from alpha(1)Ala(291) to alpha(1)Val(307). The ability of these mutants to react with the water-soluble, sulfhydryl-specific reagent pCMBS(-) was assayed electrophysiologically. Cysteines substituted for alpha(1)Ala(291) and alpha(1)Tyr(294) reacted with pCMBS(-) applied both in the presence and in the absence of GABA. Cysteines substituted for alpha(1)Phe(298), alpha(1)Ala(300), alpha(1)Leu(301), and alpha(1)Glu(303) only reacted with pCMBS(-) applied in the presence of GABA. We infer that the pCMBS(-) reactive residues are on the water-accessible surface of the protein and that GABA induces a conformational change that increases the water accessibility of the four M3 residues, possibly by inducing the formation of water-filled crevices that extend into the interior of the protein. Others have shown that mutations of alpha(1)Ala(291), a water-accessible residue, alter volatile anesthetic and ethanol potentiation of GABA-induced currents. Water-filled crevices penetrating into the interior of the membrane-spanning domain may allow anesthetics and alcohol to reach their binding sites and thus may have implications for the mechanisms of action of these agents.

4-Chloromercuribenzenesulfonate↗
PubMed1976

Mass fragmentographic quantitation of glutamic acid and gamma-aminobutyric acid in cerebellar nuclei and sympathetic ganglia of rats.

A method for the simultaneous quantitation of glutamic acid and gamma-aminobutyric acid (GABA) in tissue by mass fragmentography has been developed. The amino and carboxylic groups of the two amino acids were in a convenient one-step reaction derivatized with pentafluoropropionic anhydride and hexafluoroisopropanol. Deuterium-labeled glutamic acid and GABA and a homologue of GABA have been used as internal standards. The usefulness of the technique has been demonstrated by measurements in parts of rat cerebellum and in the superior cervical ganglion.

Aminobutyrates↗
PubMed2003

Presynaptic gamma-aminobutyric acid type B receptor-mediated regulation of vesicular gamma-aminobutyric acid transporter expression in the gerbil hippocampus.

Changes in vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) expression in the gerbil hippocampus after treatment with baclofen (GABA(B) receptor agonist) or phaclofen (GABA(B) receptor antagonist) were investigated to identify the GABA(B) receptor-mediated regulation of VGAT expression. In the baclofen-treated seizure-resistant gerbils, VGAT expression was significantly reduced, as compared with the control animals, thus the VGAT immunoreactive pattern in these gerbils was similar to that in control seizure-sensitive (SS) gerbils. In the phaclofen-treated SS gerbils, VGAT expression was dramatically elevated, compared to SS gerbil controls. Our findings demonstrated that GABA(B) receptor-mediated regulation of VGAT expression may be another mechanisms for presynaptic GABA release, which is accompanied by a reduction in Ca(2+) conductance by the inhibition of voltage-gated Ca(2+) channels.

Animals↗
PubMed1982

Decreased CSF concentrations of homovanillic acid and gamma-aminobutyric acid in Alzheimer's disease. Age- or disease-related modifications?

Fifteen patients, 48 to 72 years old, with Alzheimer's disease were studied. Clinical status was assessed by neurologic and neuropsychologic examinations and psychometric testing. Patients were divided into two groups on the basis of clinical assessment: group 1, little mental deterioration, and group 2, serious mental deterioration. Nineteen subjects, 27 to 72 years old, without neurologic disease served as controls. Levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and gamma-aminobutyric acid (GABA) were determined in lumbar CSF by fluorimetric or radioreceptor binding (GABA) methods. The HVA concentrations increased with age in the controls, whereas the GABA levels decreased with age and 5-HIAA levels were not modified. When compared with the age-matched controls, the patients with Alzheimer's disease showed low concentrations of HVA but not of 5-HIAA or GABA. The decrease in HVA level was more pronounced in patients with severe mental deterioration and therefore appeared to be disease related.

Age Factors↗
PubMed1981

Sulfur amino acid metabolism in the developing rhesus monkey brain: subcellular studies of taurine, cysteinesulfinic acid decarboxylase, gamma-aminobutyric acid, and glutamic acid decarboxylase.

Taurine, cysteinesulfinic acid decarboxylase (CSAD), glutamate, gamma-aminobutyric acid (GABA), and glutamic acid decarboxylase (GAD) were measured in subcellular fractions prepared from occipital lobe of fetal and neonatal rhesus monkeys. In addition, the distribution of [35S]taurine in subcellular fractions was determined after administration to the fetus via the mother, to the neonate via administration to the mother prior to birth, and directly to the neonate at various times after birth. CSAD, glutamate, GABA, and GAD all were found to be low or unmeasurable in early fetal life and to increase during late fetal and early neonatal life to reach values found in the mother. Taurine was present in large amounts in early fetal life and decreased slowly during neonatal life, arriving at amounts found in the mother not until after 150 days of age. Significant amounts of taurine, CSAD, GABA, and GAD were associated with nerve ending components with some indication that the proportion of brain taurine found in these organelles increases during development. All subcellular pools of taurine were rapidly labeled by exogenously administered [35S]taurine. The subcellular distribution of all the components measured was compatible with the neurotransmitter or putative neurotransmitter functions of glutamate, GABA, and taurine. The large amount of these three amino acids exceeds that required for such function. The excess of glutamate and GABA may be used as a source of energy. The function of the excess of taurine is still not clear, although circumstantial evidence favors an important role in the development and maturation of the CNS.

Aging↗
PubMed1984

Pharmacological properties of new cyclic derivatives of phenylsuccinimide and their influence on noradrenaline, dopamine, serotonin, 5-hydroxyindoleacetic acid, gamma-aminobutyric acid concentrations and monoaminooxidase activity in animal brains.

Three new cyclic derivatives of phenylsuccinimide (I-10, I-11 and IL-7) were subjected to preliminary pharmacological studies in animals. Minimal peripheral action and inhibitory influence on the CNS were noted (only IL-7) was found to stimulate CNS). Neurotoxic effects were similar to those of the classical succinimides . Anticonvulsant activity and behavioral effects of tested compounds are discussed in the light of their influence on neurotransmitters.

Animals↗
PubMed1986

Differences in anionic dependence of the synaptic efflux of D-aspartic acid and gamma-aminobutyric acid.

The synaptosomal effluxes of D-aspartate and gamma-aminobutyric acid (GABA) induced by a substitution of the Cl- ions with propionate in the incubation medium were measured in preparations of hippocampal tissue homogenates. The efflux of aspartate was significantly higher than spontaneous efflux at 125 mM Cl- (normal = 144 mM) and was increased with decreasing Cl- concentration. GABA efflux was much less sensitive to a reduction in Cl- concentration than D-aspartate. The efflux was Ca2+-dependent in both cases.

Animals↗
PubMed1985

Effect of excitatory amino acids on gamma-aminobutyric acid release from frog horizontal cells.

The effects of excitatory amino acids, analogues and K on [3H]gamma-aminobutyric acid [3H]GABA) release from horizontal cells of the isolated superfused frog retina were studied. Exposure of the retina to medium containing high concentrations (25-100 mM) of KCl increased the release of [3H]GABA to a maximum which was 40 times the spontaneous resting release. The K-evoked release of [3H]GABA was almost abolished in high-Mg/low-Ca medium. Glutamate, aspartate, kainate and quisqualate also stimulated the release of [3H]GABA from horizontal cells, the maximum evoked release being similar to that produced by KCl. The release of [3H]GABA evoked by glutamate, aspartate, kainate and quisqualate was abolished in high-Mg/low-Ca medium and by Na-free medium. The evoked releases of [3H]GABA were not reduced by tetrodotoxin. N-Methyl-D-aspartate (NMDA) at concentrations up to 10 mM had virtually no effect on [3H]GABA release from horizontal cells. In Mg-free medium, NMDA stimulated [3H]GABA release, but the maximum release was only 10% of that produced by other agonists. Mg-free medium did not significantly affect the evoked release of [3H]GABA by other agonists. NMDA apparently possessed affinity for the kainate receptor, because in normal medium it antagonized the effects of kainate but not glutamate, aspartate or quisqualate. The non-selective antagonist of excitatory amino acids, (+/-)-cis-2,3-piperidine dicarboxylic acid (PDA) antagonized the action of glutamate, aspartate, kainate and quisqualate on horizontal cell [3H]GABA release. D(-)-2-Amino-4-phosphonobutyrate (APB) and D-gamma-glutamylglycine (D-gamma-GG) antagonized the actions of kainate on horizontal cell [3H]GABA release at concentrations which had little affect on quisqualate-evoked responses. Approximate estimates of pA2 values (Schild, 1947) showed that the specificity and potency of the antagonists was low. Nevertheless, the retinal 'non-NMDA' receptors can probably be subdivided into kainate and quisqualate types. Glutamate diethylester (GDEE) did not affect the action of any agonist. We conclude that glutamate (and aspartate) probably stimulate the release of [3H]GABA from frog horizontal cells by activating receptors of the non-NMDA type. This activation may trigger the opening of tetrodotoxin-insensitive Na channels, resulting in the depolarization of the cell membrane and an increase in the conductance of voltage-sensitive Ca-channels. An influx of Ca ions would then trigger the release of [3H]GABA. Our results are not consistent with previous suggestions that GABA release from horizontal cells involves an outwardly directed transport process.

Amino Acids↗
PubMed1982

Hydroxy- and amino-substituted piperidinecarboxylic acids as gamma-aminobutyric acid agonists and uptake inhibitors.

The syntheses of (3RS,4RS)-4-hydroxypiperidine-3-carboxylic acid (4), (3RS,5SR)-5-hydroxypiperidine-3-carboxylic acid (20), (3RS,4SR)-4-acetamidopiperidine-3-carboxylic acid (10), and (3RS,5SR)-5-acetamidopiperidine-3-carboxylic acid (18), related to the specific gamma-aminobutyric acid (GABA) uptake inhibitors (RS)-piperidine-3-carboxylic acid (nipecotic acid) and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21), are described. Furthermore, (3RS,4SR)-3-hydroxypiperidine-4-carboxylic acid (14), related to the specific GABA agonist piperidine-4-carboxylic acid (isonipecotic acid), has been synthesized. The structures of 4, 10, 14, 18, and 20 have been established by 270-MHz 1H NMR spectroscopic analyses. The affinity of the compounds for the GABA receptors and for the neuronal (synaptosomal) GABA uptake system in vitro has been measured. Compound 14 interacts selectively with the GABA receptors but less effectively than isonipecotic acid and the cis-isomer 22. Compounds 4, 18, and 20 are inhibitors of the GABA uptake system, although much weaker than nipecotic acid and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21). Compound 10 is inactive in both test systems.

Animals↗
PubMed1988

Possible coexistence of amino acid (gamma-aminobutyric acid), amine (dopamine) and peptide (substance P); neurons containing immunoreactivities for glutamic acid decarboxylase, tyrosine hydroxylase and substance P in the hamster main olfactory bulb.

The coexistence of immunoreactivities for glutamic acid decarboxylase (GAD), tyrosine hydroxylase (TH) and substance P (SP) was revealed in the hamster main olfactory bulb, using the peroxidase-antiperoxidase immunohistochemical method. Adjacent 40 micron thick Vibratome sections were incubated in different antisera and those cells which were bisected by the plane of sectioning were identified at the paired surfaces of two consecutive sections. The coexistence of the immunoreactivities for 1) TH and GAD, 2) TH and SP and 3) GAD and SP in the same cells could thus be determined by observing the immunoreactivity of the two halves of the cell incubated in two different antisera. About 70% of TH-like immunoreactive (TH-LI) neurons in the periglomerular region also contained GAD-like immunoreactivity, whereas about 45% of GAD-LI ones were also TH-like immunoreactive. Furthermore, almost all (more than 95%) of SP-LI neurons contained both GAD-like and TH-like immunoreactivities. These observations indicate that in the periglomerular region of the hamster main olfactory bulb, some neurons (about 9% of all neurons containing TH-like and/or GAD-like immunoreactivities) may contain three different categories of neuroactive substances, that is, amino acid (GABA), amine (dopamine) and peptide (SP).

Animals↗
PubMed1985

gamma-Aminobutyric acid esters. 2. Synthesis, brain uptake, and pharmacological properties of lipid esters of gamma-aminobutyric acid.

Two lipid esters of U-14C-labeled and unlabeled gamma-aminobutyric acid (GABA) were synthesized to test the possibility that natural lipid analogues, which resemble normal components of lipid bilayer membranes, can penetrate the blood-brain barrier and transport exogenous GABA to the brain. The uptake of 1-linolenoyl-2,3-bis(4-aminobutyryl)propane-1,2,3-triol and 1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol into mouse brain relative to liver was found to be, respectively, 75- and 127-fold greater than that of free GABA. The results indicate that there is little or no blood-brain barrier for the GABA ester molecules at doses up to 0.36 mmol/kg. Both ester compounds, but neither free GABA nor the lipid components delivered systemically, demonstrated central nervous system depressant properties by inhibiting the general motor activity of mice. Brain tissue has esterase activity which can release GABA from these compounds. This suggests that these compounds function as "prodrugs" to release GABA in the CNS.

Animals↗
PubMed1996

Carrier-mediated gamma-aminobutyric acid uptake in human spermatozoa indicating the presence of a high-affinity gamma-aminobutyric acid transport protein.

Human spermatozoa are capable of a carrier-mediated gamma-aminobutyric acid (GABA) uptake. The uptake is dependent on the concentration of Cl- and Na+ in the external medium, and the kinetics of the carrier resembles high-affinity GABA transport proteins. The time-dependent uptake of GABA displays large interindividual differences and is not correlated to motility parameters or morphology in the individual sample. Incubation of human spermatozoa with radiolabeled GABA was performed. Swim-up preparations of human spermatozoa were incubated with [3H]GABA, and subsequent GABA uptake was measured at various times by scintillation counting. GABA was accumulated intracellularly, and the uptake could be inhibited by preincubation of the samples in 200 microM nipecotic acid. Addition of aminooxyacetic acid in the medium did not alter the results, indicating that the internalized GABA remained unmetabolized intracellularly throughout the observation period. Kinetic analysis of GABA uptake was performed, and the Km for GABA transport was 14 microM. GABA uptake was reduced by equimolar substitution of NaCl in the capacitating medium by KCl, choline chloride, LiCl, N-methyl-D-glucamine (HCl) or D-glucuronic acid (sodium salt). Maximal reduction of [3H]GABA uptake was observed when the Na+ fraction of the medium was replaced with KCl. The results indicate the presence of a high-affinity GABA transport protein in the plasma membrane of human spermatozoa. GABA uptake was subsequently measured in 30 individual semen samples from men of barren couples. Large interindividual differences in GABA uptake was observed, but GABA uptake was not correlated to motility parameters or to morphology in the individual samples analyzed.

Carrier Proteins↗
PubMed1985

Effect of aminooxyacetic acid on gamma-aminobutyric acid release from frog retina.

The Ca2+-dependence of the release of [3H]gamma-aminobutyric acid (GABA) from the pre-loaded, superfused frog retina was investigated in the presence and absence of the GABA-transaminase inhibitor, aminooxyacetic acid (AOAA). In the latter case, an ion-exchange column chromatographic technique was used to separate [3H]GABA from tritiated metabolites released with it into the superfusate. In the presence of aminooxyacetic acid, a 2 min 30 mM K+ pulse released similar amounts of [3H]GABA in normal and Ca2+-free Ringer solutions. However, when aminooxyacetic acid was absent, the K+-evoked release of [3H]GABA was substantially reduced under Ca2+-free conditions. It is concluded that the presence of aminooxyacetic acid can reduce the Ca2+-dependence of K+-evoked release of GABA from the frog retina. This is in accordance with its effect on cerebral cortex of the rat, reported previously.

Acetates↗
PubMed1981

Substituted 4-aminobutanoic acids. Substrates for gamma-aminobutyric acid alpha-ketoglutaric acid aminotransferase.

Substituted 4-aminobutanoic acids were studied as potential irreversible inactivators of purified pig brain gamma-aminobutyric acid aminotransferase, the enzyme responsible for the degradation of the inhibitory neurotransmitter, gamma-aminobutyric acid. It was found that unlike the related 4-amino-5-halopentanoic acids (Silverman, R. B., and Levy, M. A. (1981) Biochemistry 20, 1197), the 4-amino-3-halobutanoic acids were substrates for this enzyme, undergoing exclusive elimination to succinic semialdehyde and producing no inactivation. The hydroxy analogue, however, underwent exclusive transamination and no succinic semialdehyde was detected. These results are discussed in terms of the nature of the substituents, the structure of the active site of gamma-aminobutyric acid aminotransferase, and the design of mechanism-based inactivators.

4-Aminobutyrate Transaminase↗
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↗