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At least 343 records · Page 19Linked to original sources
PubMed1981

Presence of radiolabelled metabolites in release studies using [3H]gamma-aminobutyric acid.

Most studies on gamma-aminobutyric acid (GABA) release from nervous tissue have been conducted using radiolabelled GABA in the presence of aminooxyacetic acid (AOAA) to inhibit GABA: 2-oxoglutarate aminotransferase (GABA-T) to prevent conversion of labelled GABA to labelled catabolites. Here we present data showing that even in the presence of 10 microM-AOAA the spontaneous release of tritium from rat cortical synaptosomes prelabelled with 2,3-[3H]GABA is mainly in the form of tritiated water but that the increase in tritium release in the presence of unlabelled GABA or high potassium-ion concentrations is in the form of authentic [3H]GABA. Interpretation of results should take these facts into account.

4-Aminobutyrate Transaminase↗
PubMed2003

[Expression of gamma-aminobutyric acid receptor gamma 1 subunit in the end-organs of rat vestibule].

OBJECTIVE: To investigate the expression of the gamma-aminobutyric acid receptor gamma 1 subunit in the end-organs of rat vestibule. METHOD: Using a combination of reverse transcription followed by polymerase chain reaction, expression of the gamma-aminobutyric acid receptor gamma 1 subunit in the end-organs of rat vestibule was examined. The rat brain RNA was used as positive control. RESULT: PCR amplification products representing subunit gene expression for gamma-aminobutyric acid receptor alpha 1 subunit were amplified. CONCLUSION: The results showed that gamma-aminobutyric acid receptor gamma 1 subunit was expressed in the rat vestibule, indicating that GABA is one of the important neurotransmitters in the vestibular system.

Animals↗
PubMed2000

Correlation of the apparent affinities and efficacies of gamma-aminobutyric acid(C) receptor agonists.

gamma-Aminobutyric acid (GABA), trans-4-aminocrotonic acid (TACA), muscimol, imidazole-4-acetic acid (I4AA), cis-4-aminocrotonic acid (CACA), and isoguvacine are all GABA(C) receptor agonists. These compounds have different apparent sensitivities (EC(50)) and efficacies (I(max)) on exogenously expressed human rho1 homomeric GABA(C) receptors. It is not clear if these differences are due to distinct binding affinities and/or distinct gating kinetics. In this study, using a recently developed single oocyte binding technique, we determined the apparent dissociation constants (K(i) values) of these compounds from their IC(50) values for [(3)H]GABA displacement. The apparent K(i) values fell into two distinct groups. The high affinity group was comprised of agonists with longer distances between the nitrogen atom of the amino or imidazole group and the carbon atom of the carboxyl or isoxazole group. The single oocyte binding technique, in conjunction with two-electrode voltage clamp, has allowed a direct correlation of the apparent affinity, efficacy, and potency of agonists on intact functional GABA(C) receptors. The correlation and coupling of these parameters are discussed in terms of a simple proposed activation mechanism.

Animals↗
PubMed2006

Immobilization and characterization of gamma-aminobutyric acid on gold surface.

gamma-Aminobutyric acid (GABA) is one of two main inhibitory neurotransmitters in the central nervous system that plays an important role in neuronal function and dysfunction. Immobilization of GABA molecules on a rigid surface in an ordered fashion will provide an opportunity to understand some of the fundamental properties related to its structure and function. In this study, we report a novel strategy for immobilization of bioactive GABA on gold substrate. GABA was immobilized in three consecutive steps, namely gold substrate amination, dextran covalent attachment, and GABA immobilization. Surface chemistry was verified at each step using XPS and FTIR. Bioactivity of GABA immobilized on the gold surface was studied using atomic force microscopy to reveal antigen-antibody binding. Nonspecific protein adsorption on the bioactive surface was analyzed quantitatively using anti-GABA antibody and an enzyme linked nonspecific anti-immunoglobulin-G antibody in an ELISA assay. GABA functionalized surface has high affinity for anti-GABA, while showing significantly low affinity for nonspecific anti-IgG antibody. All these data support the presence of a bio-functional immobilized GABA on the gold surface. In conclusion, we report a novel technique for immobilizing bioactive GABA molecules in an orderly fashion on gold substrates.

Coated Materials, Biocompatible↗
PubMed1980

Inhibition of transmitter release in bullfrog sympathetic ganglia induced by gamma-aminobutyric acid.

1. Effects of gamma-aminobutyric acid (GABA) on the nicotinic synapses in bullfrog sympathetic ganglia were studied. 2. When GABA (100 microM--1 mM) was applied to the ganglion, the post-synaptic membrane depolarized slightly and transiently with a slight decrease in the membrane resistance. 3. GABA (5 microM--1 mM) decreased the amplitude of the fast excitatory post-synaptic potentials (fast e.p.s.p.) and its quantal content without a significant change in the quantal size, and these effects were seen even after the subsidence of the membrane depolarization. Picrotoxin (10 microM) did not antagonize the GABA action. 4. The sensitivity of the subsynaptic membrane to ACh was unaffected by GABA. On the other hand, the synaptic current underlying the fast e.p.s.p. was significantly depressed in the presence of GABA. 5. Neither the frequency nor the amplitude of the miniature e.p.s.p.s which occurred spontaneously were altered by GABA, in either normal or high K+ solutions. 6. The depressant action of GABA on the fast e.p.s.p. was not changed in a high K+ solution, while it was markedly decreased in a Cl- -deficient solution. 7. A small, but significant reduction in the amplitude of the presynaptic terminal spike recorded with a focal extracellular electrode was observed under the effect of GABA. 8. It was concluded that GABA inhibits synaptic transmission of bullfrog sympathetic ganglion mainly by decreasing the evoked release of transmitter and only partly by post-synpatic action. Possible mechanisms of the presynaptic action of GABA were discussed.

Acetylcholine↗
PubMed1998

Regulation of gastrin, somatostatin and bombesin release from the isolated rat stomach by exogenous and endogenous gamma-aminobutyric acid.

BACKGROUND/AIMS AND METHODS: gamma-Aminobutyric acid (GABA) is localized in epithelial cells and intrinsic nerve fibers of the gastric mucosa raising the possibility of a regulatory role for this transmitter. Therefore, it was the aim of the present study to examine the effect of exogenous and endogenous GABA on the neuroendocrine functions of the isolated perfused rat stomach. RESULTS: Infusion of GABA (10(-8), 10(-6), 10(-4) M) caused a significant increase in gastrin release by 187 +/- 98, 328 +/- 43 and 493 +/- 84 pg/20 min and a significant decrease in somatostatin secretion by -540 +/- 203, -867 +/- 96 and -893 +/- 195 pg/20 min, respectively. Release of bombesin-like immunoreactivity (BLI) remained unchanged during infusion of GABA at the concentrations employed. The gastrin and somatostatin responses to 10(-4) M GABA were completely inhibited by the GABA(A) antagonist bicuculline (10(-5) M) and the cholinergic blocker atropine(l0(-7) M), whereas the GABAB antagonist CGP 35348 (5 x 10(-5) M) was ineffective. To evaluate the contribution of endogenous GABA in the vagal regulation of gastric neuroendocrine functions, gastrin, somatostatin and BLI responses to electrical stimulation of the vagal nerves were examined in the presence of bicuculline. Vagal stimulation (10 V, 10 Hz, 1 ms) induced a significant inhibition of somatostatin release by - 518 +/- 78 pg/10 min, which was attenuated to -259 +/- 143 pg/10 min (p < 0.05) in the presence of bicuculline. Atropine (10(-7) M) turned vagally induced inhibition of somatostatin release into a stimulation by 928 +/- 266 pg/10 min which was not altered by additionally infused bicuculline. Vagally stimulated gastrin release was reduced from 397 +/- 47 to 217 +/- 72 pg/10 min (p < 0.05) by bicuculline, while atropine had no effect. Vagally induced BLI release was not altered by bicuculline and atropine. Since the effect of bicuculline on vagally induced gastrin release was independent of cholinergic mechanisms, a potential direct effect of GABA on gastrin release was examined in isolated rabbit antral G cells. In this preparation carbachol (10(-4) M) and neuromedin C (10(-9) M) significantly stimulated gastrin release from 2.6 +/- 0.4 to 4.9 +/- 0.3 and 8.5 +/- 0.9% of the total cellular content, respectively, while GABA (10(-10)-10(-3) M) changed neither basal nor carbachol- and neuromedin C-stimulated gastrin release. CONCLUSION: The present data confirm that exogenous GABA stimulates gastrin release and inhibits somatostatin release from the isolated rat stomach via GABA(A) receptors by activating cholinergic neurotransmission. Furthermore, it was shown for the first time that endogenous GABA contributes to the vagal regulation of gastrin and somatostatin release from the rat stomach. Inhibition of somatostatin secretion by endogenous GABA is mediated by cholinergic mechanisms, whereas stimulation of gastrin release is mediated by pathways unrelated to the cholinergic system and bombesin peptides.

Animals↗
PubMed1984

An N-protected gamma-aminobutyric acid dipeptide with anticonvulsant action.

N-Pivaloyl-leucyl-gamma-aminobutyric acid (PLG) is a synthetic dipeptide with a partition coefficient of 1.67 in an ethyl acetate/water system that partially inhibits the synaptosomal uptake and activates the release of [U-14C]gamma-aminobutyric acid [( U-14C]GABA). The displacement of GABA from crude synaptic membranes by PLG occurs with an IC50 of 10(-5) M. The compound has the capacity to cross the blood-brain barrier and increase central GABA levels. Its ED50 on cardiazol -induced convulsions is 60-65 mg/kg. PLG is resistant to hydrolysis by chymotrypsin and partially inhibits the proteolytic activity of trypsin.

Animals↗
PubMed1999

Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.

GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine alpha1-subunit gene, that alpha1-type GABA(A) receptors, which are mainly expressed in cortical areas and thalamus, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter gamma-aminobutyric acid is preserved. alpha1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABA(A) receptors found in the limbic system (alpha2, alpha5), in monoaminergic neurons (alpha3) and in motoneurons (alpha2, alpha5). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.

Animals↗
PubMed1985

[Concentrations of free and bound 4-aminobutyric acid in human serum: reference values].

A rapid and sensitive procedure is described for the quantification of gamma-aminobutyric acid in human plasma, using ion-exchange fluorescence. Analytical values for gamma-aminobutyric acid vary according to the method of deproteinization, storage conditions and sample treatment. A practicable and precise method for the evaluation of free and bound gamma-aminobutyric acid is presented. The mean concentration of the free neurotransmitter in neurologically normal control subjects was 142.4 +/- 13.1 nmol/l (n = 30). The mean concentration of the bound form was 438.6 +/- 51.1 nmol/l in the same subgroup.

Adolescent↗
PubMed2006

Discrimination of hairpin polyamides with an alpha-substituted-gamma-aminobutyric acid as a 5'-TG-3' reader in DNA minor groove.

Pyrrole-imidazole (Py-Im) polyamides containing stereospecifically alpha-amino- or alpha-hydroxyl-substituted gamma-aminobutyric acid as a 5'-TG-3' recognition element were synthesized by machine-assisted Fmoc solid-phase synthesis. Their binding properties to predetermined DNA sequences containing a core binding site of 5'-TGCNCA-3'/3'-ACGN'GT-5' (N.N' = A.T, T.A, G.C, and C.G) were then systematically studied by surface plasmon resonance (SPR). SPR results revealed that the pairing of stereospecifically alpha-amino-/alpha-hydroxyl-substituted gamma-aminobutyric acids, (R or S)-alpha,gamma-diaminobutyric acid (gammaRN or gammaSN) and (R or S)-alpha-hydroxyl-gamma-aminobutyric acid (gammaRO or gammaSO), side-by-side with beta-alanine (beta) in such polyamides significantly influenced the DNA binding affinity and recognition specificity of hairpin polyamides in the DNA minor groove compared with beta/beta, beta/gamma, and gamma/beta pairings. More importantly, the polyamide Ac-Im-gammaSO-ImPy-gamma-ImPybetaPy-beta-Dp (beta/gammaSO) favorably binds to a hairpin DNA containing a core binding site of 5'-TGCNCA-3'/3'-ACGN'GT-5' (N.N' = A.T) with dissociation equilibrium constant (K(D)) of 1.9 x 10(-)(7) M over N.N' = T.A with K(D) = 3.7 x 10(-)(6) M, with a 19-fold specificity. By contrast, Ac-Im-gammaSN-ImPy-gamma-ImPybetaPy-beta-Dp (beta/gammaSN) binds to the above sequence with N.N' = A.T with K(D) = 8.7 x 10(-)(7) M over N.N' = T.A with K(D) = 8.4 x 10(-)(6) M, with a 9.6-fold specificity. The results also show that the stereochemistry of the alpha-substituent, as well as the alpha-substituent itself may greatly alter binding affinity and recognition selectivity of hairpin polyamides to different DNA sequences. Further, we carried out molecular modeling studies on the binding by an energy minimization method, suggesting that alpha-hydroxyl is very close to N3 of the 3'-terminal G to induce the formation of hydrogen bonding between hydroxyl and N3 in the recognition event of the polyamide Ac-Im-gammaSO-ImPy-gamma-ImPybetaPy-beta-Dp (beta/gammaSO) to 5'-TGCNCA-3'/3'-ACGN'GT-5' (N.N' = A.T). Therefore, SPR assays and molecular modeling studies collectively suggest that the (S)-alpha-hydroxyl-gamma-aminobutyric acid (gammaSO) may act as a 5'-TG-3' recognition unit.

Binding Sites↗
PubMed2006

Effects of beer and hop on ionotropic gamma-aminobutyric acid receptors.

Beer induced the response of the ionotropic gamma-aminobutyric acid receptors (GABA(A) receptors) expressed in Xenopus oocytes, indicating the presence of gamma-aminobutyric acid (GABA)-like activity. Furthermore, the pentane extract of the beer, hop (Humulus lupulus L.) oil, and myrcenol potentiated the GABA(A) receptor response elicited by GABA. The GABA(A) receptor responses were also potentiated by the addition of aliphatic esters, most of which are reported to be present in beer flavor. Aliphatic esters showed the tendency to decrease in the potentiation of the GABA(A) receptor response with an increase in their carbon chain length. When myrcenol was injected to mice prior to intraperitoneal administration of pentobarbital, the pentobarbital-induced sleeping time of mice increased additionally. Therefore, the beer contained not only GABA-like activity but also the modulator(s) of the GABA(A) receptor response.

Acyclic Monoterpenes↗
PubMed1982

Gamma-aminobutyric acid can both inhibit and facilitate dopamine release in the caudate nucleus of the rabbit.

Slices from rabbit caudate nucleus were preincubated with [3H]dopamine and then superfused and stimulated electrically. gamma-Aminobutyric acid (10-4) and 10(-3) mol/L increased both the basal and the stimulation-evoked overflow of tritium. The effects were not changed by picrotoxin and were only slightly reduced by bicuculline. In the presence of nipecotate 10(-3) mol/L, gamma-aminobutyric acid decreased rather than enhanced the basal and the evoked overflow. The inhibition persisted in the presence of bicuculline. Muscimol did not affect, whereas baclofen decreased, the evoked overflow of tritium. Similar results obtained with synaptosomes that were stimulated by 30 mmol/L K+. The results indicate that gamma-aminobutyric acid can both facilitate and depress the release of dopamine. Facilitation occurs after entry of gamma-aminobutyric acid into the dopaminergic terminal axons, whereas inhibition if probably mediated by a receptor site located in the membrane of these terminals.

Animals↗
PubMed1998

Inhibition of capsaicin-induced cough by the gamma-aminobutyric acid agonist baclofen.

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA-agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14-day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low-dose, oral baclofen given once daily. Forty-one healthy volunteers were randomly assigned in a double-blind manner to receive a 28-day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once-daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA-agonists as potential therapeutic agents for chronic, nonproductive cough.

Administration, Oral↗
PubMed2004

Selection of stable RNA molecules that can regulate the channel-opening equilibrium of the membrane-bound gamma-aminobutyric acid receptor.

The gamma-aminobutyric acid (GABA(A)) receptor belongs to a superfamily of membrane-bound proteins that regulate signal transmission between cells in the nervous system. It is the target of convulsants such as picrotoxin and is mutated in some forms of epilepsy, a disease affecting approximately 50 million people worldwide. In picrotoxin inhibition and in one form of epilepsy, a decrease in the channel-opening equilibrium of a GABA(A) receptor is responsible for receptor dysfunction. Here we identify compounds that can regulate the channel-opening equilibrium of the GABA(A) receptor. Fluorinated RNA polymers containing a 40-nucleotide region with a randomized sequence were used to select those that can displace picrotoxin from the membrane-bound GABA(A) receptor in the rat forebrain. After 11 selection rounds, two classes of RNA molecules that bind to the GABA(A) receptor with nanomolar affinity were isolated and sequenced. Class I and class II molecules have different consensus sequences and different binding affinities for the receptor. A transient kinetic technique, the cell-flow method, was employed in combination with the whole-cell current-recording technique to determine the affinity of the selected RNA aptamers for the GABA(A) receptor. Class I molecules have a higher affinity for the closed-channel form than for the open-channel receptor form and inhibit the receptor; class II aptamers bind with equal or higher affinity to the open-channel form and alleviate picrotoxin inhibition.

Animals↗
PubMed1983

Phosphorylation induces a decrease in the biological activity of the protein inhibitor (GABA-modulin) of gamma-aminobutyric acid binding sites.

gamma-Aminobutyric acid (GABA)-modulin is a brain protein of Mr 16,500 that down-regulates the high-affinity binding site for GABA which is located in crude synaptic membranes. This protein can be phosphorylated in vitro by the catalytic subunit of cAMP-dependent protein kinase and by a partially purified preparation of calmodulin-sensitive Ca2+-dependent protein kinase. The GABA-modulin sites that are phosphorylated by the two enzymes are different, as revealed by HPLC analysis of tryptic digests. The capacity of GABA-modulin to decrease the number of sites that bind [3H]muscimol was completely abolished by phosphorylation of this protein with the cAMP-dependent protein kinase but not with the Ca2+-dependent enzyme. GABA-modulin present in crude synaptic membranes prepared from rat cortex also was shown to be phosphorylated by endogenous protein kinases activated by cAMP, Ca2+ and calmodulin, and Ca2+ and phosphatidylserine. These results suggest a potentially important role for protein kinase and GABA-modulin in the regulation of the number of GABA recognition sites.

Animals↗
PubMed1978

Relationship between gamma-aminobutyric acid metabolism and antivitamin B6-induced convulsions.

The correlation between the gamma-aminobutyric acid (GABA) metabolism and convulsions by some vitamin B6 antagonists, DL-penicillamine (PeA), hydrazine (Hyd), thiosemicarbazide (TSC) were investigated. Glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) activities were inhibited during convulsions by three antagonists, and GABA content was not changed by PeA, increased by Hyd and decreased by TSC in mice whole brain. In subcellular fractions of brain, GAD activity was inhibited and GABA content decreased in synaptosomes during convulsions by the above three drugs. Aminooxyacetic acid (AOAA), a potent GABA-elevating agent, showed an anticonvulsant property against convulsions by TSC for several hours after the injection of AOAA, but lost this property 16hr after treatment. During the convulsions by TSC 16hr after the AOAA-pretreatment, the GABA content in synaptosomes was less than that from the group treated with AOAA alone, though its GABA level was higher than the normal level. From the above results, the GABA content and GAD activity in synaptosomes might be deeply associated with convulsions by B6 antagonists.

4-Aminobutyrate Transaminase↗