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PubMedDate not supplied

Carbon and nitrogen sources regulate delta-aminolevulinic acid and gamma-aminobutyric acid transport in Saccharomyces cerevisiae.

Evidence has been obtained showing that transport of delta-aminolevulinic acid (ALA), a precursor of porphyrin biosynthesis in Saccharomyces cerevisiae, is mediated by the gamma-aminobutyric acid (GABA)-specific permease, UGA4. In yeast GABA is also incorporated by the general amino acid permease (GAP1) and the specific proline permease (PUT4). The aim of the present work was to carry out a comparative study on the regulation of ALA and GABA transport to confirm our proposal that both compounds share the UGA4 permease. ALA and GABA uptake were measured in cells grown on minimal media with different carbon and/or nitrogen sources. To study the effect of the carbon source on UGA4 permease, ALA and GABA incorporation were measured in D27 strain, lacking GAP1 permease, and grown in proline as the sole nitrogen source, so the activity of PUT4 permease was negligible. The effect of the nitrogen source on UGA4 permease was studied measuring ALA and GABA uptake rates in cells from media with ammonium, proline and urea as nitrogen sources. It was found that the regulation by the carbon source was similar on ALA and GABA transport; they depend equally on the energetic conditions of the cells. Moreover, regulation by the nitrogen source on ALA and GABA uptake was also similar, and identical to that described already for UGA4 permease. These results are further evidence that both compounds, ALA and GABA, share the GABA-specific permease, UGA4.

Aminolevulinic Acid↗
PubMed1980

Influence of cellular transport on the interaction of amino acids with gamma-aminobutyric acid (GABA)-receptors in the isolated olfactory cortex of the guinea-pig.

1 Freshly cut guniea-pig olfactory cortex slices contained 2.2 mmol gamma-aminobutyric acid (GABA)/kg tissue weight. This declined during in vitro incubation at 25 degrees C in the absence of exogenous GABA, but increased to 6.95 mmol/kg after 1.5 h incubation in 1 mM GABA. 2 Uptake of [3H]-GABA (1 microM) was inhibited by 1 mM (+/-)-nipecotic acid (-83%), beta-amino-n-butyric acid (BABA) (-59%), L-2,4-diaminobutyric acid (DABA) (-63%), (+/-)cis-3-aminocyclohexane carboxylic acid (ACHC) (-53%), and 3-aminopropanesulphonic acid (3-APS) (-26%), but was increased by beta-alanine (BALA) (+23%). 3 Autoradiographs showed steep concentration gradients of radioactivity across slices incubated for short periods in [3H]-GABA. 4 Efflux of [3H]-GABA from pre-loaded slices was accelerated strongly by nipecotic acid, BABA, DABA and ACHC but weakly or not all by BALA or 3-APS. 5 Nipecotic acid (1 mM) potentiated the surface-depolarization of the slice produced by GABA but not that produced by 3-APS. 6 The depolarizing actions of DABA, BABA, nipecotic acid and ACHC, but not that of 3-APS or BALA, were potentiated when the endogenous GABA content of slices was raised. 7 It is concluded that: (a) the depolarizing action of exogenous GABA is limited by cellular uptake; (b) surface-depolarizations produced by nipecotic acid, DABA, BABA and ACHC may be mediated by the release of GABA; and (c) neuronal, rather than glial, transport systems are responsible for these effects.

Amino Acids↗
PubMed1983

Group-selective reagent modification of the benzodiazepine-gamma-aminobutyric acid receptor-ionophore complex reveals that low-affinity gamma-aminobutyric acid receptors stimulate benzodiazepine binding.

The modification of membrane proteins with diethylpyrocarbonate (DEP) and diazotized sulfanilate was investigated on the binding of three benzodiazepine radioligands in three brain regions. Both of these reagents produced a dose-dependent inactivation of [3H] diazepam, [3H]flunitrazepam, and [3H]propyl beta-carboline-3-carboxylate binding to cortex, cerebellum, and hippocampus. Both DEP and diazotized sulfanilate decrease the Bmax of the benzodiazepine binding sites without altering the KD. The ability of muscimol and pentobarbital to enhance [3H]diazepam binding was not altered by DEP pretreatment in any of the three regions. Scatchard analysis indicated that, following the inactivation of 40-50% of [3H]diazepam binding by 1 mM DEP, pentobarbital and muscimol were still able to increase the affinity of [3H]diazepam binding in cortex, cerebellum, and hippocampus. In contrast, diazotized sulfanilate pretreatment abolishes the ability of muscimol and pentobarbital to enhance [3H]diazepam binding in these three regions. The effects of these reagents on [3H] gamma-aminobutyric acid (GABA) binding revealed that sulfanilate but not DEP eliminates the low-affinity GABA receptor sites in cortex and cerebellum. Thus, while both DEP and sulfanilate inactivate benzodiazepine binding sites, only sulfanilate abolishes the low-affinity GABA binding sites and the ability of the GABA agonists to enhance [3H]diazepam binding. These results suggest that the stimulation of benzodiazepine binding appears to be mediated by the low-affinity GABA receptors.

Animals↗
PubMed1976

Huntington's disease: treatment with dipropylacetic acid and gamma-aminobutyric acid.

Dipropylacetic acid (DPA), and anticonvulsant known to raise brain gamma-aminobutyric acid (GABA), was administered orally to eight patients with Huntington's disease. Both alone and in combination with high oral doses of GAGA, DPA failed to ameliorate and motor signs of this disorder. At maximum dose levels, combined DPA and GABA treatment led to an apparent increase in the central turnover of both dopamine and serotonin, as estimated by the oral probenecid-loading test. These latter observations may indicate a close functional interrelation between monoaminergic and GABAnergic neural pathways in the central nervous system of man.

Adult↗
PubMed1995

Visual evoked potentials N75 and P100 latencies correlate with urinary delta-aminolevulinic acid, suggesting gamma-aminobutyric acid involvement in their generation.

Pattern reversal visual evoked potentials were recorded from 31 subjects who were occupationally exposed to lead and 54 non-exposed controls. No significant effects of lead were observed in the general subject population. However, when only non-smokers (17 lead-exposed and 27 controls) were evaluated, significant effects were found. The P100, but not the N75, latency was significantly prolonged in the lead-exposed group, and this correlated with both blood lead level and age. Nevertheless, both the N75 and P100 latencies correlated with the concentration of delta-aminolevulinic acid (delta-ALA) in urine and age. This, at least in part, could be due to elevated delta-ALA levels competing at gamma-aminobutyric acid (GABA) receptor neurons. This is consistent with the fact that GABA receptor neurons are involved along the entire length of the visual pathway. The results indicate that lead affects neural function even at permitted levels of exposure, and that this level should be reduced.

Aminolevulinic Acid↗
PubMed1971

Competitive interaction of beta-guanidino propionic acid and gamma-aminobutyric acid on the muscle fibre of the crayfish.

1. The interaction of beta-guanidino propionic acid and gamma-aminobutyric acid has been investigated on the crayfish muscle by measurement of the membrane conductance.2. The increase in membrane conductance produced by GABA is depressed by beta-guanidino propionic acid. This antagonist acts in a competitive way as shown by the shift of log dose-response curves and by the results of tests for competitive interaction (method of Schild (1947); Lineweaver and Burk's plot).3. Perfusion of GABA was shown to induce a receptor desensitization. As a consequence, the slope of the dose-response curve plotted in Hill's co-ordinates increases when care is taken to minimize this phenomenon. The significance of this slope for establishing the real number of GABA molecules binding with the GABA receptor is discussed.

Aminobutyrates↗
PubMedDate not supplied

Overestimation of serum concentrations of gamma-aminobutyric acid in patients with hepatic encephalopathy by the gamma-aminobutyric acid-radioreceptor assay.

Sera of patients with hepatic encephalopathy strongly inhibit the specific binding of gamma-aminobutyric acid to synaptic membranes. In a previous study, this inhibition of specific gamma-aminobutyric acid binding was attributed to gamma-aminobutyric acid itself, and it was assumed that serum gamma-aminobutyric acid is increased 5- to 30-fold in patients with hepatic encephalopathy. The findings of that study, however, were not confirmed by other analytical methods. Therefore, the validity of the gamma-aminobutyric acid-radioreceptor assay was tested. In view of the increased serum concentrations of several amino acids in hepatic encephalopathy, the effects of L-alpha-amino acids on the assay were studied. Five amino acids inhibited specific gamma-aminobutyric acid binding at a concentration of 0.5 mM or lower: glutamine; glutamate; taurine; proline, and OH-proline. Equimolar amounts of aminooxyacetate prevented the inhibition of specific gamma-aminobutyric acid binding by glutamine and glutamate but had no effect on that of gamma-aminobutyric acid, taurine, proline and OH-proline. Aminooxyacetate had no effect on specific gamma-aminobutyric acid binding itself. The inhibitory activity of a serum sample from a patient with hepatic encephalopathy was inhibited by 0.5 mM aminooxyacetate. The gamma-aminobutyric acid binding inhibitory activity of a serum sample of a patient with hepatic encephalopathy was purified by gel chromatography and contained several amino acids at concentrations of about 0.1 mM, 3.5 mM glutamine but no detectable gamma-aminobutyric acid. Accordingly, the gamma-aminobutyric acid binding inhibitory activity is not mediated by gamma-aminobutyric acid alone and is most likely due to glutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1966

Aminooxyacetic acid: interactions with gamma-aminobutyric acid and the blood-brain barrier.

The hypothesis that the administration of aminooxyacetic acid, a competitive inhibitor of aminobutyrate aminotransferase, might allow gamma-aminobutyric acid to cross the blood-brain barrier was tested by analyzing the brains of rats for this compound after intraperitoneal injection of aminooxyacetic acid, or a mixture of both acids, and by observing behavioral and physiological changes in cats after similar drug administrations. The results do not support the postulate that gamma-aminobutyric acid enters the brain more readily after administration of aminooxyacetic acid.

Acetates↗
PubMed1981

Influence of sodium-independent gamma-aminobutyric acid binding on the assay of sodium-dependent gamma-aminobutyric acid binding in a membrane preparation of rat brain.

A large amount of [3H]GABA was bound to crude synaptic membrane fractions of rat, by sodium-independent process in a medium that contained 100 microM [3H]GABA used for assaying GABA uptake site. This [3H]-GABA binding was different from receptor binding of GABA. It was confirmed that this sodium-independent [3H]GABA binding scarcely occurred in the presence of a physiological concentration of sodium chloride, and that sodium-independent GABA binding had a negligible influence on sodium-dependent GABA binding.

Animals↗
PubMed1984

Embryonic cerebellar neurons accumulate [3H]-gamma-aminobutyric acid: visualization of developing gamma-aminobutyric acid-utilizing neurons in vitro and in vivo.

gamma-Aminobutyric acid (GABA) is the proposed neurotransmitter for four types of cerebellar neurons-Purkinje, Golgi, basket, and stellate neurons. With this investigation we have begun studies to establish when these neurons acquire their neurotransmitter "identification." Autoradiographic studies of both cultured embryonic (embryonic day 13) cerebellar cells and of intact embryonic cerebellum (embryonic day 13) were conducted with tritiated GABA. Two to 5% of the embryonic cerebellar cells accumulated [3H]GABA in vitro. By morphological and immunocytochemical criteria, labeled cells were large neurons with either a thick, apical process, a multipolar shape, or were bipolar with longer processes. The identification of cells which accumulated [3H]GABA as neuronal precursors was supported by the differential sensitivity to drugs that preferentially inhibit accumulation of [3H]GABA by neurons and glia. The results of the in vitro experiments were confirmed and extended with in vivo experiments. When intact cerebellar tissue was removed at embryonic day 13, stripped of meninges and choroid plexus, exposed to low concentrations of [3H]GABA, and processed for light microscopic autoradiography, heavily labeled cells were seen in the middle of the cerebellar anlage. Labeled cells were not seen in the ventricular zone of proliferating neuroblasts lining the fourth ventricle or in the external granular layer emerging at the lateral aspect of the pial surface. The accumulation of [3H]GABA by these cells also showed the pharmacological characteristics of uptake by neurons. This study shows that among migrating, immature forms of the larger neurons of the embryonic cerebellum, there is a select group which accumulates [3H]GABA and other classes of cells which do not. These results indicate very early acquisition of transmitter expression by cerebellar neurons, far in advance of their final positioning and establishment of synapses.

Animals↗
PubMed1986

In vivo action of enzyme-activated irreversible inhibitors of glutamic acid decarboxylase and gamma-aminobutyric acid transaminase in retina vs. brain.

The effects of low s.c. doses of gamma-acetylenic gamma-aminobutyric acid (GAG) on glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) activities, as well as of gamma-vinyl GABA (GVG) and gabaculine on GABA-T activities, were examined using preparations from retina and several other regions of rat central nervous system (CNS). GAG, in doses of 5 to 50 mg/kg, inactivated retinal GAD to a significantly greater degree than GAD from any other CNS region studied. Retinal GABA-T activities were also differentially inactivated by 1 to 50 mg/kg of GAG, 50 mg/kg of GVG, or 1 and 5 mg/kg of gabaculine. GAG, in doses of 25 and 50 mg/kg, more completely inactivated GAD and GABA-T in frontal cortex than in other brain regions. Frontal cortical GABA-T was not differentially inactivated by 10 and 50 mg/kg of GVG or 1 and 5 mg/kg of gabaculine. The effects of GAG on retinal GABA enzymes were long-lasting and not reversed by dialysis. The GAD and GABA-T activities from 1:1 mixes of control and GAG-treated retinal preparations were comparable to the means of the GAG-treated and control activities. The effects documented in this study, therefore, probably reflect irreversible in vivo changes. After peripheral administration, GAG, GVG and gabaculine might reach higher levels in the retina than in the brain. Alternatively, the differential effects of these compounds might be due to the relative proportions of catalytically active GABA enzymes in different CNS regions. On the basis of the foregoing results, the retina might be a particularly suitable region of the CNS for enzyme-activated irreversible inhibitors to label catalytically active enzymes of GABA metabolism.

4-Aminobutyrate Transaminase↗
PubMed1995

A single amino acid in gamma-aminobutyric acid rho 1 receptors affects competitive and noncompetitive components of picrotoxin inhibition.

A class of bicuculline-insensitive gamma-aminobutyric acid (GABA) receptors, GABAC, has been identified in retina. Several lines of evidence indicate that GABAC receptors are formed partially or wholly of GABA rho subunits. These receptors generate a Cl- current in response to GABA but differ from GABAA receptors in a number of ways. Picrotoxin, widely accepted as a noncompetitive antagonist of GABAA receptors, displays competitive and noncompetitive antagonism of GABAC receptors in perch and bovine retina and GABA rho 1 receptors expressed in Xenopus oocytes. The aim of this study was to identify the molecular basis of the two components of picrotoxin inhibition of GABA rho 1 receptors. By using a domain-swapping and mutagenesis strategy, a difference in picrotoxin sensitivity between rho 1 and rho 2 receptors was localized to a single amino acid in the putative second transmembrane domain. Substitution of this amino acid with residues found in the analogous position in highly picrotoxin-sensitive glycine alpha and GABAA subunits increased the sensitivity of rho 1 mutants 10- to 500-fold. Importantly, the competitive component of picrotoxin inhibition of the rho 1 mutant receptors was almost eliminated. These findings demonstrate that an amino acid in the putative channel domain of GABA rho 1 receptors influences picrotoxin sensitivity and mediates agonist binding by an allosteric mechanism.

Animals↗
PubMed1994

Possible intermolecular interaction between quinolones and biphenylacetic acid inhibits gamma-aminobutyric acid receptor sites.

The combination of some new quinolone antibacterial agents with 4-biphenylacetic acid (BPAA), a metabolite of fenbufen, is known to specifically induce functional blockade of the gamma-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further examined. Scatchard analysis of [3H]muscimol binding to rat brain plasma membranes in the presence of enoxacin and BPAA revealed that a significant decrease in the number of muscimol binding sites was produced without affecting the affinity of binding to the receptors. In the presence of norfloxacin, BPAA inhibited muscimol binding the most potently of the six BPAA-related compounds tested. Fenbufen and 9,10-dihydro-gamma-oxo-2-phenanthrenebutyric acid also inhibited the binding, and 4-biphenylcarboxylic acid and methyl 4-biphenylacetate inhibited it slightly, but 3-benzoylpropionic acid exhibited no competitive inhibition. Accordingly, hybrid molecules of norfloxacin and BPAA were synthesized for stereochemical analysis of these drug interactions. A hybrid with a -CONH(CH2)3- chain between norfloxacin and BPAA (flexible structure) inhibited muscimol binding, and intracisternal injection of this hybrid caused clonic convulsions in mice more potently than the combination of norfloxacin and BPAA did. In contrast, a hybrid linked by -CONH- (stretched structure) showed almost no such inhibitory effect. 1H NMR analysis indicated the presence of intramolecular attraction at the quinoline ring of the hybrid exhibiting the antagonistic activity. These results suggest the possibility that quinolones and BPAA interact with the GABA receptor at nearby sites and that the binding affinity of quinolones to the GABA receptors is largely enhanced by the intermolecular interaction with BPAA.

Animals↗
PubMed1995

Interaction between striatal excitatory amino acid and gamma-aminobutyric acid (GABA) receptors in the turning behaviour of rats.

N-Methyl-D-aspartate (NMDA, 500 ng/0.5 microliters), alpha-amino-3-hydroxy-5-methyl-4-isoxasole-propionic acid (AMPA, 1000 ng/0.5 microliters), or kainic acid (50 ng/0.5 microliters) injected into intermediate and caudal parts of the caudate-putamen induced contralateral head turns and rotations. Picrotoxin (250 ng/0.5 microliters) injected into the same striatal region 30 min before NMDA, AMPA, or kainic acid strongly increased the contralateral turning induced by each of those compounds. The present results suggest that blockade of gamma-aminobutyric acid (GABA)A receptor complex by picrotoxin rendered striatal neurons more sensitive to the action of glutamate on NMDA and non-NMDA receptors.

Animals↗
PubMed1987

[Interaction of muscle glycogen phosphorylase b with nicotinic acid, nicotinamide, N-nicotinyl-gamma-aminobutyric acid and nicotinamide coenzymes].

The inhibitory action of nicotinic acid, nicotinamide, N-nicotinoyl-gamma-aminobutyric acid, NAD, NADH, NADP, and NADPH on the rabbit skeletal muscle glycogen phosphorylase b has been studied. The inhibition is reversible and positively cooperative (the value of Hill coefficients were determined for the following compounds: nicotinic acid (28 mM; 1.4), nicotinamide (4.4 mM; 1.2), N-nicotinoyl-gamma-aminobutyric acid (9.5 mM; 1.4), NAD (4.4 mM; 1.2), NADH (0.93 mM; 1.2). NADH-binding site of glycogen phosphorylase b subunit was characterized by the sedimentation velocity method. Microscopic dissociation constant was found to be 86 +/- 9 microM (pH 6.8; 20 degrees C). AMP-induced association of glycogen phosphorylase b is hindered by NADH.

Animals↗